Reversal of general anesthesia by administration of methylphenidate, amphetamine, modafinil, amantadine, and/or caffeine

ABSTRACT

The present invention generally relates to compositions comprising anesthesia-reversing agents which facilitate or increase the time of awakening or reverse the effects of general anesthesia-induced unconsciousness. In some embodiments, the anesthesia reversing agent can be selected from any or a combination of methylphenidate (MPH), amphetamine, modafinil, amantadine, caffeine, or analogues or derivatives thereof. In some embodiments, compositions comprising at least one or more anesthesia-reversing agents can be used to facilitate awakening from anesthesia without or decreasing occurrence of delirium, and can be used in methods to treat or prevent the symptoms associated with emergence delirium, as well as treat a subject oversedated with general an esthesia. The invention also relates to methods for administering these compositions comprising anesthesia-reversing agents to subjects and for use.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. 119(e) of U.S.Provisional Patent Application Ser. No. 61/378,977 filed on Sep. 1,2010, and U.S. Provisional Patent Application Ser. No. 61/483,475 filedon May 6, 2011, the contents of each are incorporated herein byreference in their entirety.

GOVERNMENT SUPPORT

The present application was made with Government Support under Grant No:DP1-OD003646, K08-GM094394 and K08-GM083216 awarded by the NationalInstitutes of Health (NIH). The Government of the United States hascertain rights thereto.

FIELD OF THE INVENTION

The present invention relates to a method and compositions for rapidlyreversing general anesthesia, and facilitates awakening of a subjectfrom general anesthesia. In particular, the present invention relates toa method and compositions for facilitating emergence or awakening fromperioperative anesthesia, and a method for controlling and facilitatinganesthesia according to the methods and compositions as disclosedherein.

BACKGROUND OF THE INVENTION

General anesthesia is a reversible coma, actively induced and maintainedby administering intravenous and inhalational drugs.¹ In contrast,emergence from general anesthesia is a slow passive process achievedsimply by allowing the effects of the drug to wear off. Emergence ofanesthesia is therefore a passive process whereby anesthetic drugs aremerely discontinued at the end of surgery, and no drugs are administeredto actively reverse their effects on the brain and central nervoussystem. That is, the general anesthetic agents are merely discontinuedat the end of surgery, leaving the anesthesiologist and surgeon to waitfor the patient to recover consciousness. The timing of emergence can beunpredictable because many factors including the nature and duration ofthe surgery, and the age, physical condition and body habitus of thepatient, can greatly affect the pharmacokinetics and pharmacodynamics ofgeneral anesthetics. Although the actions of many drugs used inanesthesiology are pharmacologically reversed when no longer desired(e.g. muscle relaxants, opioids, benzodiazepines, and anticoagulants),this is not the case for general anesthetic induced loss ofconsciousness.

This current clinical paradigm of passive emergence is dangerous becausepatients are highly susceptible to potentially severe complications suchas laryngospasm, respiratory depression, hemodynamic instability, anddelirium. In addition, operating room (OR) time, estimated to costbetween $12.37 to $17.11 per minute at MGH, is an expensive resourcethat is squandered during the time spent waiting for patients to emergefrom general anesthesia.

At present, there is no agent available to actively induce emergencefrom general anesthesia. This is largely due to our limited knowledge ofthe molecular mechanisms of general anesthetic actions, hampering thedevelopment of drugs that antagonize the actions of general anesthetics.However, accumulating evidence suggests that ascending arousal pathwaysin the brain can play important roles in emergence from generalanesthesia.² While cholinergic,^(3,4) Aorexinergic,⁵ and histaminergic⁶arousal pathways have been implicated in emergence, the roles of otherarousal pathways are yet unknown. Methylphenidate is widely prescribedfor the treatment of Attention Deficit Hyperactivity Disorder (ADHD) inchildren and adults, and acts primarily by inhibiting the dopamine andnorepinephrine reuptake transporters,⁷ thereby increasing dopaminergicand adrenergic neurotransmission. Recently, methylphenidate has alsobeen reported to increase prefrontal cortex histamine levels in rats.⁸Dopamine, norepinephrine, and histamine are monoamine neurotransmittersthat promote arousal through pathways emanating from nuclei in the pons,midbrain and hypothalamus.^(2,9)

SUMMARY OF THE INVENTION

The present invention relates to agents which function as generalanesthesia emerging agents for a method to awaken a subject from generalanesthesia. In some embodiments, the anesthesia-reversing agents asdisclosed herein are useful as a “rescue” drug, or a method to rescuesubjects who are accidentally oversedated and become unresponsive orapneic during conscious sedation.

One embodiment of the present invention relates to a method of reducingthe effects of general anesthesia in a subject (e.g., a human patient)treated with a general anesthetic agent comprising administering to thesubject an effective amount of a composition comprising ananesthesia-reversing agents as disclosed herein, thereby reducing theeffects of general anesthesia in the subject. In some embodiments, ananesthesia-reversing agent can be selected from one or more or anycombination of: methylphenidate (MPH), amphetamine, modafinil,amantadine, caffeine or a product containing any of these agents. Insome embodiments, amphetamine is dextro-amphetamine (D-amphetamine). Insome embodiments, amphetamine is levo-amphetamine (L-amphetamine). Insome embodiments, a composition can comprise a plurality ofanesthesia-reversing agents, e.g., at least 2 or at least 3, or at least4, or at least 5, or at least 6, or at least 7, or moreanesthesia-reversing agents.

Without wishing to be limited to theory, the effects of generalanesthesia induces the subject to unconsciousness, and emerge fromanesthesia occurs as a passive process after withdrawal or cessation ofanesthesia administration. The present invention providesanesthesia-reversing agents and methods of use to greatly facilitate thespeed of emergence from general anesthesia, and restoration of mobilityor consciousness in the subject, without waiting for the passive processof the general anesthesia agents to wear off. The present invention ofusing the anesthesia-reversing agents as disclosed herein reduces theeffects of general anesthesia thereby reduces or eliminates the effectsof emergence delirium in the subject.

In some embodiments, the compositions comprising theanesthesia-reversing agents, and their method of use to awaken a subjectfrom anesthesia can be used to reverse a subject from any form ofanesthesia agent. In some embodiments, the anesthetic agent isisoflurane; which results in unconsciousness or diminished arousal inthe subject, and in some embodiments, the compositions comprising theanesthesia-reversing agents, and their method of use can be used toreverse the unconsciousness or diminished arousal in the subject.

Herein, the inventors have demonstrated that methylphenidate (MPH) andanalogues and derivatives thereof induces emergence of a subject fromanesthesia-induced unconsciousness, e.g., from isoflurane or propofolinduced anesthesia and other anesthesia agents in rats by increasingarousal and respiratory drive. Accordingly, one aspect of the presentinvention relates to use of methylphenidate as a clinically useful as anagent to reverse general anesthetic-induced unconsciousness andrespiratory depression at the end of surgery.

Accordingly, in one embodiment, an anesthesia-reversing agent is MPH,and in some embodiments, MPH is dextro-methylphenidate (D-MPH). In someembodiments, a methods and compositions as disclosed herein can compriseD-MPH and L-MPH anesthesia-reversing agents. In some embodiments, themethods and compositions as disclosed herein can comprise D-MPH andL-MPH anesthesia-reversing agents in equal or different ratios, e.g.,about 50%:50%, or about 60%:40%, or about 70%:30%, or 80%:20%, 90%:10%,95%:5% etc. or any other ratio, of D-MPH:L-MPH or vice versa, e.g., ofL-MPH:D-MPH.

In some embodiments, compositions comprising the anesthesia-reversingagents, and their method of use to reverse the anesthesia of a subjectcan be administered by intravenous dose. In some embodiments,compositions comprising the anesthesia-reversing agents, and theirmethod of use to awaken a subject from anesthesia can be administered byany form, e.g., by inhalation and the like.

One aspect of the present invention relates to a method of facilitatingemergence from general anesthesia in a subject treated with a generalanesthetic agent comprising administering to the subject an effectiveamount of a composition comprising at least one anesthesia-reversingagent, wherein the anesthesia-reversing agent facilitates emergence ofthe subject from the general anesthesia. In some embodiments, theanesthesia-reversing agent is selected from any or a combination ofmethylphenidate (MPH), amphetamine, modafinil, amantadine, or caffeine.In some embodiments, the anesthesia-reversing agent is amethylphenidate, which is dextro-methylphenidate (D-MPH) orlevo-methylphenidate (L-MPH) or a combination thereof, or an analogue orderivative thereof. In some embodiments, the methylphenidate is racemicmethylphenidate. In some embodiments, the anesthesia-reversing agent isamphetamine, which can be L-amphetamine.

In some embodiments, the emergence of the subject from generalanesthesia comprises restoration of mobility or consciousness in thesubject, and/or reducing or eliminating the effects of delirium onemergence of the subject from the general anesthesia.

In some embodiments, the anesthesia-reversing agent is effective atfacilitating awakening or emergence from anesthesia, e.g., from ageneral anesthetic agent which is administered to the subject byinhalation anesthesia. In some embodiments, a general anesthetic agentis selected from any, or a combination of isoflurane, propofol,halogenate gasses, ketamine, sevoflurane, desflurane, sodium pentothal,or etomidate, and other anesthetics commonly known to persons ofordinary skill in anesthesia.

In some embodiments, the anesthesia-reversing agent is administered tothe subject by intravenous dose, or alternative embodiments, theanesthesia-reversing agent is administered to the subject by inhalation.In some embodiments, the anesthesia-reversing agent is administered tothe subject in combination or concurrently with at least one additionaltherapeutic agent, such as, but not limited to a pain-reducing agent orgeneral analgesic, such as but not limited to a opioids and otherpost-surgery anesthetics. In some embodiments, the pain-reducing agentor general analgesic comprises an anesthesia-reducing agent as disclosedherein, e.g., caffeine.

In some embodiments, the subject is a perioperative anesthetizedpatient. In some embodiments, the subject is no longer beingadministered an anesthesia agent, e.g., isoflurane or other anesthesiaagent. In alternative embodiments, a subject can be administered thecomposition comprising the anesthesia-reversing agent immediately priorto cessation of administration an anesthesia agent. In such embodiments,the dose of the anesthesia agent can be reduced with an inverserelationship with the increasing dose of the anesthesia-reversing agentas disclosed herein, so that, for example, the dose of the anesthesiaagent is reduced concurrently with an increase in the dose of theanesthesia-reversing agent as disclosed herein. In alternativeembodiments, a subject can be administered the composition comprisingthe anesthesia-reversing agent subsequent to, and in some instances,immediately upon cessation of administration an anesthesia agent, suchthat as soon as the anesthesia agent is stopped being administered, thesubject is administered at least one anesthesia-reversing agent.

In some embodiments, the dose of an anesthesia-reversing agent asdisclosed herein is administered at a higher dose than ordinary andacute use of the anesthesia-reversing agent for a disease or condition,e.g., for sleep disorders or ADHD. In some embodiments, the dose of ananesthesia-reversing agent is at least about 10%, or at least about 30%,or at least about 40%, or at least about 50% or at least about 75% or atleast about 2-fold or at least about 3-fold, or at least about 5-fold orhigher than 5-fold higher than the ordinary use of ananesthesia-reversing agent, e.g., for the treatment of an acutedisorder, disease or condition. In some embodiments, a subject can beadministered a higher dose of methylphenidate than the dose used for thetreatment of Attention Deficit Disorder (ADD) or Attention DeficitHyperactivity Disorder (ADHD) in the subject. As discussed above, thedose of a methylphenidate used as an anesthesia-reversing agentaccording to the methods as disclosed herein, can be at least aboutleast about 30%, or at least about 40%, or at least about 50% or atleast about 75% or at least about 2-fold or at least about 3-fold, or atleast about 5-fold or higher than 5-fold higher than the dose ofmethylphenidate used in the treatment of Attention Deficit Disorder(ADD) or Attention Deficit Hyperactivity Disorder (ADHD). In someembodiments, a dose of methylphenidate can be between about 10 mg/kg andabout 5 mg/kg, and any integer between about 5 mg/kg and 10 mg/kg. Insome embodiments, the dose is between about 7 mg/kg and about 0.1 mg/kg,or between about 5 mg/kg and about 0.5 mg/kg.

In some embodiments, the anesthesia-reversing agent is administered tothe subject via continuous administration. In alternative embodiments,the anesthesia-reversing agent can be administered to the subject viapulse administration.

Another aspect of the present invention relates to the use of ananesthesia-reversing agent for the preparation of a medicant forreversing general anesthesia-induced unconsciousness in a subject, wherethe anesthesia-reversing agent can be selected from any or a combinationof methylphenidate (MPH), amphetamine, modafinil, amantadine, etomidateor caffeine, according to the methods and composition as disclosedherein. In some embodiments, the medicant comprises methylphenidatewhich is selected from dextro-methylphenidate (D-MPH) orlevo-methylphenidate (L-MPH) or a combination thereof, or an analogue orderivative thereof. In some embodiments, the medicant comprises racemicmethylphenidate. In some embodiments, the medicant comprisesamphetamine, which can be L-amphetamine. In some embodiments, themedicant is prepared as an intravenous medicant, and in someembodiments, the medicant is prepared as an inhalation medicant.

BRIEF DESCRIPTION OF THE DRAWINGS

This patent or application file contains at least one drawing executedin color. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIGS. 1A-1B show methylphenidate (MPH) decreases time to emergence fromisoflurane anesthesia. FIG. 1A shows rats inhaled isoflurane (1.5%) fora total of 45 minutes, and received normal saline or methylphenidate (5mg/kg IV, solid arrow) five minutes before removal from theanesthetizing chamber (dashed arrow). Time to emergence was defined asthe time from termination of isoflurane to return of righting (i.e. allfour paws touching the floor). FIG. 1B shows a scatter plot of time toemergence for rats that received normal saline vs. methylphenidate (5mg/kg IV). The line represents the median. ***P<0.0001.

FIGS. 2A-2D show methylphenidate induces emergence during continuousinhalation of isoflurane. FIG. 2A shows that rats which inhaledisoflurane at a dose sufficient to maintain loss of righting for a totalof 40 minutes, and received normal saline. Five minutes later,methylphenidate was administered IV. Isoflurane was continued at thesame dose until return of righting occurred or 30 minutes elapsed. FIG.2B shows a dose-dependence of methylphenidate-induced emergence. FIG. 3Cshows a scatter plot of time to righting for rats that received 0.5versus 5 mg/kg IV of methylphenidate. The line represents the median.FIG. 2D shows that after pretreatment with droperidol (0.5 mg/kg IV)instead of normal saline, high-dose methylphenidate (5 mg/kg IV) did notinduce return of righting in any of the six animals tested. ***posteriorprobability>0.95, *P<0.05.

FIGS. 3A-3B shows methylphenidate-induced electroencephalogram changesduring continuous inhalation of isoflurane are inhibited by droperidol.FIG. 3A shows thirty-second epochs of electroencephalogram recordingsfrom a single rat show the change from an active, theta-dominant patternduring the awake state to the delta-dominant pattern during inhalationof isoflurane (1.0%). The latter pattern is unchanged after theadministration of normal saline. Administration of methylphenidate (5mg/kg IV) induced a prompt shift in the electroencephalogram back to anactive theta-dominant pattern similar to that observed during the awakestate. This pattern persisted for more than 15 minutes. FIG. 3B showsthirty-second epochs of raw electroencephalogram recordings from adifferent animal than (FIG. 3A) show the same patterns during the awakeand anesthetized states. Administration of droperidol (0.5 mg/kg IV)induced no appreciable change in the electroencephalogram pattern.However, when methylphenidate (5 mg/kg IV) was administered five minutesafter droperidol, the electroencephalogram did not return to the active,theta-dominant pattern observed during the awake state. Rather, thedelta-dominant pattern persisted.

FIGS. 4A-4C show spectral analysis of electroencephalogram data revealsa shift in power induced by methylphenidate that is inhibited bydroperidol. Warm colors (e.g. red) represent higher power at a givenfrequency, while cool colors (e.g. blue) represent lower power. FIG. 4Ashows a representative spectrogram computed from a rat in the awakestate shows predominance of theta power (4-8 Hz). FIG. 4B shows arepresentative spectrogram computed from a rat inhaling isoflurane(1.0%) shows predominance of delta power (<4 Hz) before and afteradministration of normal saline. However, administration ofmethylphenidate (5 mg/kg IV) promptly induced a shift in power to anactive theta-dominant pattern similar to that observed during the awakestate. This animal began to move vigorously approximately 5 minutesafter methylphenidate administration, generating significant motionartifacts. Therefore the experiment was promptly terminated. FIG. 4Cshows a representative spectrogram computed from a rat that receiveddroperidol (0.5 mg/kg IV) instead of normal saline shows that similar tothe rat in (FIG. 4B), delta power is dominant during inhalation ofisoflurane (1.0%), before and after administration of droperidol.However, after administration of droperidol, methylphenidate (5 mg/kgIV) did not induce a shift in electroencephalogram to the theta-dominantpattern characteristic of the awake state. In addition, this animalshowed no purposeful movement after methylphenidate administration.

FIGS. 5A-5B show an electroencephalogram power spectra and spectrogramscomputed for each of 4 animals reveal a shift in peak power from deltato theta after administration of methylphenidate that is inhibited bydroperidol. The top panel shows the two-minute windows used to computepower spectra before methylphenidate administration (red, “PRE”), andafter methylphenidate administration (blue, “POST”). FIG. 5A showsspectrograms and power spectra computed from animals that receivednormal saline prior to methylphenidate (MPH). Power spectra show resultsof the Kolmogorov-Smirnov test for the two-minute periods before andafter methylphenidate administration. At a 0.05 significance level (withBonferonni correction) the Kolmogorov-Smirnov test rejects the nullhypothesis at all frequencies except those marked with white squares.Statistically significant changes occurred at most frequencies between0-10 Hz. (The fourth animal moved during the time window used for theanalysis, and therefore motion artifact may account for the persistenthigh delta power observed after methylphenidate administration in thisanimal.) FIG. 5B shows spectrograms and power spectra computed fromanimals that received droperidol prior to methylphenidate (MPH). Afterdroperidol, methylphenidate only induced statistically significantdecreases in delta power.

FIGS. 6A-6B show methylphenidate induces an increase in respiratory ratethat is inhibited by droperidol. FIG. 6A shows a time series ofrespiratory rate (filled circles) and tidal volume (open squares)recorded from one animal during inhalation of isoflurane (1.5%). Normalsaline and methylphenidate (5 mg/kg IV) were administered at theindicated times. Methylphenidate induced a prompt and sustained increasein respiratory rate from 103 to 154 breaths per minute (p<10-16), whiletidal volume remained essentially unchanged. FIG. 6B shows when adifferent animal was pretreated with droperidol (0.5 mg/kg IV) insteadof normal saline, methylphenidate induced little change in respiratoryrate or tidal volume.

FIG. 7 show dexo-methylphenidate (D-MPH) decreases time to emergencefrom isoflurane anesthesia at a quicker rate than L-MPH.

FIG. 8 shows EEG spectral analysis of the righting of a rat asdemonstrated by a shift in power from delta (<4 Hz) to theta (4-8 Hz)after administration of MPH during continuous propofol anesthesia.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compositions comprisinganesthesia-reversing agents and methods of their use for facilitatingemergence of a subject from anesthesia-induced unconsciousness andrestoring the subject back to consciousness and cognitive function. Thepresent invention provides several advantages, including but not limitedto decreasing time required to consciousness after general anesthesia,decreased delirium after anesthesia and the like. In some embodiments,an anesthesia-reversing agent is selected from at least one or acombination of methylphenidate (MPH), amphetamine, modafinil,amantadine, caffeine, or analogues or derivatives thereof.

Definitions

For convenience, certain terms employed herein, in the specification,examples and appended claims are collected here. Unless statedotherwise, or implicit from context, the following terms and phrasesinclude the meanings provided below. Unless explicitly stated otherwise,or apparent from context, the terms and phrases below do not exclude themeaning that the term or phrase has acquired in the art to which itpertains. The definitions are provided to aid in describing particularembodiments, and are not intended to limit the claimed invention,because the scope of the invention is limited only by the claims. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs.

The term “treating”, as used herein, refers to altering the diseasecourse of the subject being treated. Therapeutic effects of treatmentinclude, without limitation, preventing occurrence or recurrence ofdisease, alleviation of symptom(s), diminishment of direct or indirectpathological consequences of the disease, decreasing the rate of diseaseprogression, amelioration or palliation of the disease state, andremission or improved prognosis.

The term “Amphetamine” includes dextro and levo amphetamine forms andall pharmaceutically acceptable amphetamine salts. Conversion typicallyinvolves metabolism.

The term “Methylphenidate” or “MPH” includes all methylphenidate opticalisomers and all pharmaceutically acceptably methylphenidate salts. Forexample “methylphenidate” includes pure dexmethylphenidate(α-phenyl-2-piperidineacetatehydrochloride, (R,R′)-(+)-) and racemicmixtures of d- and l-methylphenidate forms.

As used herein, a “prodrug” refers to compounds that can be convertedvia some chemical or physiological process (e.g., enzymatic processesand metabolic hydrolysis) to an active compound. A prodrug may beinactive when administered to a subject, i.e. an ester, but is convertedin vivo to an active compound, for example, by hydrolysis to the freecarboxylic acid or free hydroxyl. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in anorganism. The term “prodrug” is also meant to include any covalentlybonded carriers, which release the active compound in vivo when suchprodrug is administered to a subject. Prodrugs of an active compound maybe prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a subject, cleaves to form a free hydroxy, free amino orfree mercapto group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of an alcoholor acetamide, formamide and benzamide derivatives of an amine functionalgroup in the active compound and the like. See Harper, “DrugLatentiation” in Jucker, ed. Progress in Drug Research 4:221-294 (1962);Morozowich et al, “Application of Physical Organic Principles to ProdrugDesign” in E. B. Roche ed. Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs, APHA Acad. Pharm. Sci. 40 (1977);Bioreversible Carriers in Drug in Drug Design, Theory and Application,E. B. Roche, ed., APHA Acad. Pharm. Sci. (1987); Design of Prodrugs, H.Bundgaard, Elsevier (1985); Wang et al. “Prodrug approaches to theimproved delivery of peptide drug” in Curr. Pharm. Design. 5(4):265-287(1999); Pauletti et al. (1997) Improvement in peptide bioavailability:Peptidomimetics and Prodrug Strategies, Adv. Drug. Delivery Rev.27:235-256; Mizen et al. (1998) “The Use of Esters as Prodrugs for OralDelivery of (3-Lactam antibiotics,” Pharm. Biotech. 11:345-365;Gaignault et al. (1996) “Designing Prodrugs and Bioprecursors I. CarrierProdrugs,” Pract. Med. Chem. 671-696; Asgharnejad, “Improving Oral DrugTransport”, in Transport Processes in Pharmaceutical Systems, G. L.Amidon, P. I. Lee and E. M. Topp, Eds., Marcell Dekker, p. 185-218(2000); Balant et al., “Prodrugs for the improvement of drug absorptionvia different routes of administration”, Eur. J. Drug Metab.Pharmacokinet., 15(2): 143-53 (1990); Balimane and Sinko, “Involvementof multiple transporters in the oral absorption of nucleosideanalogues”, Adv. Drug Delivery Rev., 39(1-3): 183-209 (1999); Browne,“Fosphenytoin (Cerebyx)”, Clin. Neuropharmacol. 20(1): 1-12 (1997);Bundgaard, “Bioreversible derivatization of drugs—principle andapplicability to improve the therapeutic effects of drugs”, Arch. Pharm.Chemi 86(1): 1-39 (1979); Bundgaard H. “Improved drug delivery by theprodrug approach”, Controlled Drug Delivery 17: 179-96 (1987); BundgaardH. “Prodrugs as a means to improve the delivery of peptide drugs”, Arfv.Drug Delivery Rev. 8(1): 1-38 (1992); Fleisher et al. “Improved oraldrug delivery: solubility limitations overcome by the use of prodrugs”,Arfv. Drug Delivery Rev. 19(2): 115-130 (1996); Fleisher et al. “Designof prodrugs for improved gastrointestinal absorption by intestinalenzyme targeting”, Methods Enzymol. 112 (Drug Enzyme Targeting, Pt. A):360-81, (1985); Farquhar D, et al., “Biologically ReversiblePhosphate-Protective Groups”, Pharm. Sci., 72(3): 324-325 (1983);Freeman S, et al., “Bioreversible Protection for the Phospho Group:Chemical Stability and Bioactivation of Di(4-acetoxy-benzyl)Methylphosphonate with Carboxyesterase,” Chem. Soc., Chem. Commun.,875-877 (1991); Friis and Bundgaard, “Prodrugs of phosphates andphosphonates: Novel lipophilic alphaacyloxyalkyl ester derivatives ofphosphate- or phosphonate containing drugs masking the negative chargesof these groups”, Eur. J. Pharm. Sci. 4: 49-59 (1996); Gangwar et al.,“Pro-drug, molecular structure and percutaneous delivery”, Des.Biopharm. Prop. Prodrugs Analogs, [Symp.] Meeting Date 1976, 409-21.(1977); Nathwani and Wood, “Penicillins: a current review of theirclinical pharmacology and therapeutic use”, Drugs 45(6): 866-94 (1993);Sinhababu and Thakker, “Prodrugs of anticancer agents”, Adv. DrugDelivery Rev. 19(2): 241-273 (1996); Stella et al., “Prodrugs. Do theyhave advantages in clinical practice?”, Drugs 29(5): 455-73 (1985); Tanet al. “Development and optimization of anti-HIV nucleoside analogs andprodrugs: A review of their cellular pharmacology, structure-activityrelationships and pharmacokinetics”, Adv. Drug Delivery Rev. 39(1-3):117-151 (1999); Taylor, “Improved passive oral drug delivery viaprodrugs”, Adv. Drug Delivery Rev., 19(2): 131-148 (1996); Valentino andBorchardt, “Prodrug strategies to enhance the intestinal absorption ofpeptides”, Drug Discovery Today 2(4): 148-155 (1997); Wiebe and Knaus,“Concepts for the design of anti-HIV nucleoside prodrugs for treatingcephalic HIV infection”, Adv. Drug Delivery Rev.: 39(1-3):63-80 (1999);Waller et al., “Prodrugs”, Br. J. Clin. Pharmac. 28: 497-507 (1989),content of all of which is herein incorporated by reference in itsentirety.

The terms “amphetamine prodrug” and “methylphenidate prodrug” refer toany product that contains either an amphetamine (CAS Reg. No. 300-62-9)or methylphenidate (CAS Reg. No. 113-45-1) compound respectivelyconjugated to a chemical moiety such that the conjugated amphetamine ormethylphenidate must undergo a conversion in a patient's body to becomethe active amphetamine or methylphenidate form.

The term “pharmaceutically acceptable excipient”, as used herein, refersto carriers and vehicles that are compatible with the active ingredient(for example, a compound of the invention) of a pharmaceuticalcomposition of the invention (and preferably capable of stabilizing it)and not deleterious to the subject to be treated. For example,solubilizing agents that form specific, more soluble complexes with thecompounds of the invention can be utilized as pharmaceutical excipientsfor delivery of the compounds. Suitable carriers and vehicles are knownto those of extraordinary skill in the art. The term “excipient” as usedherein will encompass all such carriers, adjuvants, diluents, solvents,or other inactive additives. Suitable pharmaceutically acceptableexcipients include, but are not limited to, water, salt solutions,alcohol, vegetable oils, polyethylene glycols, gelatin, lactose,amylose, magnesium stearate, talc, silicic acid, viscous paraffin,perfume oil, fatty acid monoglycerides and diglycerides, petroethralfatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.The pharmaceutical compositions of the invention can also be sterilizedand, if desired, mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like, which do not deleteriously react withthe active compounds of the invention.

Thus, as used herein, the term “pharmaceutically acceptable salt,” is asalt formed from an acid and a basic group of a compound of theinvention. Illustrative salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutarnate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate salts.

The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of the invention having an acidic functionalgroup, such as a carboxylic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. Other pharmaceutically acceptable salts are described in theHandbook of Pharmaceutical Salts. Properties, Selection, and Use (P.Heinrich Stahl and C. Wermuth, Eds., Verlag Helvetica Chica Acta,Zurich, Switzerland (2002)).

The term “Pharmaceutically acceptable salts” includes derivatives of thedisclosed compounds, e.g., methylphenidate (MPH), amphetamine,modafinil, amantadine, caffeine wherein the parent compound is modifiedby making non-toxic acid or base addition salts thereof, and furtherrefers to pharmaceutically acceptable solvates, including hydrates, ofsuch compounds and such salts. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid additionsalts of basic residues such as amines; alkali or organic addition saltsof acidic residues such as carboxylic acids; and the like, andcombinations comprising one or more of the foregoing salts. Thepharmaceutically acceptable salts include non-toxic salts and thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, non-toxic acidsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; otheracceptable inorganic salts include metal salts such as sodium salt,potassium salt, cesium salt, and the like; and alkaline earth metalsalts, such as calcium salt, magnesium salt, and the like, andcombinations comprising one or more of the foregoing salts.

Pharmaceutically acceptable organic salts include salts prepared fromorganic acids such as acetic, trifluoroacetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like; organic amine saltssuch as triethylamine salt, pyridine salt, picoline salt, ethanolaminesalt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt, and the like; and amino acid saltssuch as arginate, asparginate, glutamate, and the like, and combinationscomprising one or more of the foregoing salts.

The term “subject” is used interchangeably herein with “patient” andrefers to a vertebrate, preferably a mammal, more preferably a primate,still more preferably a human. Mammals include, without limitation,humans, primates, wild animals, rodents, feral animals, farm animals,sports animals, and pets. Primates include chimpanzees, cynomologousmonkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents includemice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and gameanimals include cows, horses, pigs, deer, bison, buffalo, felinespecies, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avianspecies, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish andsalmon. Patient or subject includes any subset of the foregoing, e.g.,all of the above, but excluding one or more groups or species such ashumans, primates or rodents. In certain embodiments of the aspectsdescribed herein, the subject is a mammal, e.g., a primate, e.g., ahuman. A subject can be male or female. Mammals other than humans canadministered a composition comprising an anesthesia-reversing agent asdisclosed herein, and thus, the methods and compositions describedherein can be used to treat domesticated animals and/or pets.

The term “therapeutically effective amount” or “effective amount” meansan amount effective, when administered to a human or non-human patient,to provide any therapeutic benefit. A therapeutic benefit may be anamelioration of symptoms, e.g., an amount effective to decrease thesymptoms of binge-eating disorder or a major depressive disorder. Incertain circumstances a patient may not present symptoms of a conditionfor which the patient is being treated. Thus a therapeutically effectiveamount of a compound is also an amount sufficient to provide asignificant positive effect on any indicia of a disease, disorder orcondition e.g. an amount sufficient to significantly reduce thefrequency and severity of binge eating behavior or depressive symptoms.A significant effect on an indicia of a disorder or condition includes astatistically significant in a standard parametric test of statisticalsignificance such as Student's T-test, where p<0.05; though the effectneed not be significant in some embodiments. Thus, with respect to theanesthesia-reversing agents as disclosed herein, a “therapeuticallyeffective amount” as used herein refers to an amount sufficient toeffect a beneficial or desired clinical result upon treatment.Specifically, the term “therapeutically effective amount” means anamount of a an anesthesia-reversing agent as disclosed herein sufficientto measurably (i) facilitate emergence of a subject fromanesthesia-induced unconsciousness or cause a measurable decrease intime from unconciousness as compared to in the absence of theanesthesia-reducing agent and/or (ii) decreased delirium on emergence ofanesthesia-induced unconsciousness, and/or decrease of time to fullcognitive function after anesthesia-induced unconsciousness.Therapeutically effective amounts will vary, as recognized by thoseskilled in the art, depending on the specific disease treated, the routeof administration, the excipient selected, and the possibility ofcombination therapy. Other therapeutically effective amounts may vary onthe subjects age, prior CNS disorders, electrolyte disturbances,temperament, surgery type and anesthesia type.

Determination of a therapeutically effective amount is well within thecapability of those skilled in the art. Generally, a therapeuticallyeffective amount can vary with the subject's history, age, condition,sex, as well as the severity, duration and type of the anesthesia used,and the medical condition in the subject, and administration of otherpharmaceutically active agents. Furthermore, therapeutically effectiveamounts will vary, as recognized by those skilled in the art, dependingon the anesthesia used, the route of administration, the excipientselected, and the possibility of combination therapy.

Physiological effects that can be measured to determine thetherapeutically effective amount of an anesthesia-reducing agent toinclude, without limitation, time to righting (e.g., rightingresponses), time to emergence from anesthesia-induced unconsciousness,monitoring on an electroencephalogram to when the subject has shiftedfrom the delta to the theta-dominant pattern of the awakened state (seeExamples disclosed herein). Relevant assays to measure such effectsinclude, without limitation, electroencephalogram, observation,spectograms, arterial blood gas and hemodynamic recordings, measurementsof respiratory rate, mean arterial blood pressure and heart rate.

The term “user” refers to a subject, patient, a medical care worker, ora pharmaceutical supplier.

The term “obtaining” as in “obtaining the compound” is intended toinclude purchasing, synthesizing or otherwise acquiring theanesthesia-reversing agent (or indicated substance or material).

The terms “decrease”, “reduced”, “reduction”, “decrease” or “inhibit”are all used herein generally to mean a decrease by a statisticallysignificant amount. However, for avoidance of doubt, “reduced”,“reduction” or “decrease” or “inhibit” means a decrease by at least 10%as compared to a reference level, for example a decrease by at leastabout 20%, or at least about 30%, or at least about 40%, or at leastabout 50%, or at least about 60%, or at least about 70%, or at leastabout 80%, or at least about 90% or up to and including a 100% decrease(e.g. absent level as compared to a reference sample), or any decreasebetween 10-100% as compared to a reference level.

The terms “increased”, “increase” or “enhance” or “activate” are allused herein to generally mean an increase by a statistically significantamount; for the avoidance of any doubt, the terms “increased”,“increase” or “enhance” or “activate” means an increase of at least 10%as compared to a reference level, for example an increase of at leastabout 20%, or at least about 30%, or at least about 40%, or at leastabout 50%, or at least about 60%, or at least about 70%, or at leastabout 80%, or at least about 90% or up to and including a 100% increaseor any increase between 10-100% as compared to a reference level, or atleast about a 2-fold, or at least about a 3-fold, or at least about a4-fold, or at least about a 5-fold or at least about a 10-fold increase,or any increase between 2-fold and 10-fold or greater as compared to areference level.

The term “statistically significant” or “significantly” refers tostatistical significance and generally means a two standard deviation(2SD) below normal, or lower, concentration of the marker. The termrefers to statistical evidence that there is a difference. It is definedas the probability of making a decision to reject the null hypothesiswhen the null hypothesis is actually true. The decision is often madeusing the p-value.

The term “substantially” as used herein means a proportion of at leastabout 60%, or preferably at least about 70% or at least about 80%, or atleast about 90%, at least about 95%, at least about 97% or at leastabout 99% or more, or any integer between 70% and 100%.

As used herein the term “comprising” or “comprises” is used in referenceto compositions, methods, and respective component(s) thereof, that areessential to the invention, yet open to the inclusion of unspecifiedelements, whether essential or not.

As used herein the term “consisting essentially of” refers to thoseelements required for a given embodiment. The term permits the presenceof additional elements that do not materially affect the basic and novelor functional characteristic(s) of that embodiment of the invention.

The term “consisting of” refers to compositions, methods, and respectivecomponents thereof as described herein, which are exclusive of anyelement not recited in that description of the embodiment.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural references unless the contextclearly dictates otherwise. Thus for example, references to “the method”includes one or more methods, and/or steps of the type described hereinand/or which will become apparent to those persons skilled in the artupon reading this disclosure and so forth.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients or reaction conditions usedherein should be understood as modified in all instances by the term“about.” The term “about” when used in connection with percentages canmean±1%.

In this application and the claims, the use of the singular includes theplural unless specifically stated otherwise. In addition, use of “or”means “and/or” unless stated otherwise. Moreover, the use of the term“including”, as well as other forms, such as “includes” and “included”,is not limiting. Also, terms such as “element” or “component” encompassboth elements and components comprising one unit and elements andcomponents that comprise more than one unit unless specifically statedotherwise.

Unless otherwise defined herein, scientific and technical terms used inconnection with the present application shall have the meanings that arecommonly understood by those of ordinary skill in the art to which thisdisclosure belongs. It should be understood that this invention is notlimited to the particular methodology, protocols, and reagents, etc.,described herein and as such can vary. The terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to limit the scope of the present invention, which is definedsolely by the claims. Definitions of common terms in immunology, andmolecular biology can be found in The Merck Manual of Diagnosis andTherapy, 18th Edition, published by Merck Research Laboratories, 2006(ISBN 0-911910-18-2); Robert S. Porter et al. (eds.), The Encyclopediaof Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology andBiotechnology: a Comprehensive Desk Reference, published by VCHPublishers, Inc., 1995 (ISBN 1-56081-569-8); Immunology by WernerLuttmann, published by Elsevier, 2006. Definitions of common terms inmolecular biology are found in Benjamin Lewin, Genes IX, published byJones & Bartlett Publishing, 2007 (ISBN-13: 9780763740634); Kendrew etal. (eds.), The Encyclopedia of Molecular Biology, published byBlackwell Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A. Meyers(ed.), Maniatis et al., Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (1982);Sambrook et al., Molecular Cloning: A Laboratory Manual (2 ed.), ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (1989);Davis et al., Basic Methods in Molecular Biology, Elsevier SciencePublishing, Inc., New York, USA (1986); or Methods in Enzymology: Guideto Molecular Cloning Techniques Vol. 152, S. L. Berger and A. R. KimmerlEds., Academic Press Inc., San Diego, USA (1987); Current Protocols inMolecular Biology (CPMB) (Fred M. Ausubel, et al. ed., John Wiley andSons, Inc.), Current Protocols in Protein Science (CPPS) (John E.Coligan, et. al., ed., John Wiley and Sons, Inc.) and Current Protocolsin Immunology (CPI) (John E. Coligan, et. al., ed. John Wiley and Sons,Inc.), which are all incorporated by reference herein in theirentireties.

It is understood that the foregoing detailed description and thefollowing examples are illustrative only and are not to be taken aslimitations upon the scope of the invention. Various changes andmodifications to the disclosed embodiments, which will be apparent tothose of skill in the art, may be made without departing from the spiritand scope of the present invention. Further, all patents, patentapplications, and publications identified are expressly incorporatedherein by reference for the purpose of describing and disclosing, forexample, the methodologies described in such publications that might beused in connection with the present invention. These publications areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing in this regard should be construed as anadmission that the inventors are not entitled to antedate suchdisclosure by virtue of prior invention or for any other reason. Allstatements as to the date or representation as to the contents of thesedocuments are based on the information available to the applicants anddo not constitute any admission as to the correctness of the dates orcontents of these documents.

Anesthesia-Reversing Agents

As disclosed herein, one aspect of the present invention relates tocompositions comprising anesthesia-reversing agents and methods of theiruse for facilitating emergence of a subject from anesthesia-inducedunconsciousness and restoring the subject back to consciousness andcognitive function. In some embodiments, an anesthesia-reversing agentis selected from at least one or a combination of methylphenidate (MPH),amphetamine, modafinil, amantadine, caffeine, or analogues orderivatives thereof.

Methylphenidate (MPH)

One aspect of the present invention relates to use of intravenousmethylphenidate (MPH, also known as RITALIN™) to rapidly reverse asubject unconscious by general anesthesia, e.g., isoflurane-induced orpropofol-induced anesthesia. Methylphenidate, referred to herein as“MPH” is also known in the art as RITALIN™, is a chiral compound thatexists in dextro- and levo-forms. (Sometimes referred to herein as“D-MPH” and “L-MPH”, respectively, or “Dmethylphenidate” and“L-methylphenidate”, respectively, but in any case, it is to beunderstood that each one of the terms “dextro-methylphenidate”, “D-MPH”,and “D-methylphenidate” are synonymous with D-threo-methylphenidate andthat each one of the terms “levo-methylphenidate”, “L-MPH”, and“L-methylphenidate” are synonymous with L-threo-methylphenidate.) Allprior work related to the post-operative arousal-promoting effects ofMPH was performed with the racemic form (i.e., a 50%/50% mixture ofD-MPH and L-MPH). Pure D-MPH (Focalin) is currently available in oralform for Attention Deficit Hyperactivity Disorder (ADHD), but it is notavailable for intravenous use. The resent inventors have now completed astudy in rats to test which form of MPH (D-MPH or L-MPH) is moreeffective in reversing isoflurane anesthesia, using the widely acceptedloss of righting reflex (LORR) to test for loss of consciousness. At anintravenous dose of 0.5 mg/kg (a typical dose of MPH reported in humanstudies), 83% of the rats that received D-MPH had restoration ofconsciousness, compared to only 33% with L-MPH.

In some embodiments, an anesthesia-reversing agents is MPH, D-MPH,L-MPH, or any pharmaceutically acceptable salt, polymorph or esterthereof.

Methylphenidate has the general chemical formula:

The arrow indicates a chemically accessible site at which labile groupsmay be added to create methylphenidate prodrugs. Amino acidmethylphenidate prodrugs may be prepared via the general methodsdescribed in U.S. Pat. No. 7,105,486 (which is incorporated herein inits entirety by reference) for the preparation of amphetamine amino acidprodrugs. Amino acid methylphenidate prodrugs may comprisemethylphenidate covalently bound to a single amino acid at thepiperidine nitrogen or bound to a di- or tri-peptide at this position.It is also a matter of routine organic synthesis to prepare carboxamideand carbamate methylphenidate prodrugs by reacting methylphenidate withan aliphatic aldehyde or aliphatic organic acid.

Methylphenidate contains a secondary amine group and amphetaminecontains an amino group both of which may be reacted to form prodrugshaving a chemical moiety covalently attached to the amine or amino groupof the parent drug compound. Prodrugs of amine-containing compounds havebeen disclosed in U.S. Patent Application No. 2007/0123468, which ishereby incorporated by reference at paragraphs [0078]-[0137] for itsteaching regarding general classes of amine prodrugs, at paragraph[0140] for its teaching regarding amphetamine and methylphenidateprodrugs, at paragraphs [0176]-[0181] for its teachings ofmethylphenidate prodrug structures, and at paragraphs [0184]-[0189] forits teaching regarding prodrugs synthesis.

Methylphenidate possesses two centers of chirality and thus can exist asfour separate optical isomers. The four isomers of methylphenidate areas follows:

Racemic methylphenidate and its individual isomers are known. See U.S.Pat. Nos. 2,507,631, 7,164,025 and 2,957,880, which are incorporatedherein in their entirety by reference, where methylphenidate can beprepared as a mixture of erythro [R*S*] and threo [R*R*] racemates,where the D-threo [or (R,R)] enantiomer has a preferred therapeuticactivity. They can be prepared by conventional techniques, and can beobtained from a variety of commercial sources. Additionally, a singleenantiomer of D-threo-methylphenidate or L-threo-methylphenidate can besynthesized according to the method as disclosed in U.S. Pat. No.7,164,025 which is incorporated herein in its entirety by reference.

Diastereomers are known in the art to possess differing physicalproperties, such as melting point and boiling point. For example, whilethe threo-racemate of methylphenidate produces the desired CentralNervous System action, the erythro-racemate contributes to hypertensiveside effects and exhibits lethality in rats.

Additional studies in animals, children and adults have demonstratedpharmacological activity in the d-threo isomer of methylphenidate(2R:2′R). See Patrick et al., J. Pharmacol. & Exp. Therap., 241:152-158(1987). The role of the 1-isomer in toxicity or adverse side effects hasnot been thoroughly examined.

Although 1-threo-methylphenidate is rapidly and stereo-selectivelymetabolized upon oral administration, intravenous administration orinhalation results in high 1-threo-methylphenidate serum levels.Srinivas et al., Pharmacol. Res., 10:14-21 (1993). Accordingly, in someembodiments, one can use the d-threo isomer (2R:2′R) of methylphenidateas an analgesic-reversing agent as disclosed herein, which issubstantially free of the 1-threo isomer, and produces a methylphenidatemedication which retains high activity levels and simultaneouslypossesses reduced euphoric effect and reduced potential for abuse amongpatients.

The 2R:2′R isomer of methylphenidate has the following structure and isdisclosed in U.S. Pat. No. 5,908,850 which is incorporated herein in itsentirety by reference.

U.S. Pat. No. 2,507,631, to Hartmann et al. describes methylphenidateand processes for making the same. U.S. Pat. No. 2,957,880, to Rometschet al. describes the conversion of.alpha.-aryl-.alpha.-piperidyl-(2)-acetic acids and derivatives thereof(including methylphenidate) into their respective racemates. Holmes etal., J. Clin. Psychiatry, 50:5-8 (1989) reported on the use of racemicmethylphenidate (RITALIN™) and dextroamphetamines in the treatment ofcognitive impairment in AIDS patients. Srinivas et al., J. Pharmacol. &Exp. Therap., 241:300-306 (1987) described use of racemicdl-threo-methylphenidate (RITALIN™) in the treatment of ADD in children.This study reported a 5-fold increase in plasma levels ofd-threo-methylphenidate in children treated with racemicmethylphenidate, but was otherwise inconclusive with regard to theefficacy of a single methylphenidate isomer at therapeuticallysignificant doses. Srinivas et al., Clin. Pharmacol. Ther., 52:561-568(1992) studied the administration of dl-threo, d-threo and1-threo-methylphenidate to children suffering from ADHD. While Srinivaset al. reported the pharmacodynamic activity of dl-threo-methylphenidateresides in the d-threo isomer, this study investigated neither theadverse side effects of the 1-threo isomer, nor the euphoric effects ofthe single isomers or racemate. Single isomer dosages below ½ of theracemate dosage were not studied. Patrick et al., J. Pharmacol. & Exp.Therap., 241:152-158 (1986) examined the pharmacology of the enantiomersof threo-methylphenidate, and assessed the relative contribution of eachisomer to central and peripheral actions of RITALIN™. Brown, G., Intl.J. Psych. Med., 25(1):21-37 (1995) reported the use of racemicmethylphenidate for the treatment of AIDS cognitive decline. Patrick etal., Psychopharmacology: The Third Generation of Progress, Raven Press,N.Y. (1987) examined the pharmacokinetics and actions of methylphenidatein the treatment of Attention Deficit Hyperactivity Disorder (ADHD).Patrick noted the d-threo isomer possesses higher activity than the1-threo isomer, and that d-threo methylphenidate may be responsible forthe therapeutic activity in the racemic drug. Aoyama et al., Clin.Pharmacol. Ther., 55:270-276 (1994) reported on the use of(+)-threo-methylphenidate in the treatment of hypersomnia. Aoyama et al.describe a correlation between sleep latency in patients and plasmaconcentration or (+)-threo-methylphenidate. The U.S. patents and patentapplications are incorporated herein in their entirety by reference.

MPH Analogues

Methylphenidate analogs are compounds have a structure highly similar tomethylphenidate, and like methylphenidate bind to the brain dopaminetransporter and affect the reuptake of dopamine in the brain, but whichhave an extended duration of action relative to methylphenidate.Methylphenidate analogs include compounds having the general formula:

where at least one of R₂ and R₄ is a non-hydrogen substituent differingfrom the group that occurs at the corresponding position inmethylphenidate and R1 and R5 are independently chosen from hydrogen,halogen, hydroxyl, C₁-C₂ alkyl, and C₁-C₂ alkoxy, and the like.Methylphenidate analogs have been disclosed in U.S. Non-provisionalPatent Application No. 2006/0100243, which is hereby incorporated byreference at paragraphs [0007]-[0021] for its teachings regarding themethylphenidate analog structures, at paragraphs [0055]-[0063] for itsteachings regarding the methylphenidate analog structure and synthesis,and at paragraphs [0083]-[0085] for its exemplary synthesis ofmethylphenidate analogs.

In some embodiments, intravenous D-MPH can be administered to a subjectupon completion of surgery as a highly effective and safe way to rapidlyreverse general anesthesia. Accordingly, this approach could lead toimproved patient safety and operating room efficiency. It is to beunderstood, however, that the present invention is not limited to usingD-MPH alone as the agent which reverses general anesthesia. In someembodiments, L-MPH alone may be used as an anesthesia-reversing agent asdisclosed herein, or a mixture of D-MPH and L-MPH may be used as suchanesthesia-reversing agent, and therefore, a composition comprising morethan one “anesthesia-reversing agent” can be used to reverse generalanesthesia, for example, a composition can comprise D-MPH and L-MPH. Insome embodiments, a composition comprises equal or substantially equalparts of D-MPH and L-MPH (i.e., exactly or about 50% D-MPH and exactlyor about 50% L-MPH). In some embodiments, racemic MPH is used. It is tobe understood, however, that in some embodiments, D-MPH and L-MPHalternatively may be present in a composition mixture in unequal orsubstantially unequal parts; therefore, the D-MPH may be present in anyamount and the L-MPH may be present in any amount. Further, one ofordinary skill in the art will recognize that a composition comprisingD-MPH and L-MPH optionally may include one or more compounds oranesthesia-reversing agents as disclosed herein other than D-MPH andL-MPH, and each one of these one or more compounds may or may not act toreverse the state of general anesthesia.

There are no drugs currently available for reversal of generalanesthesia at the end of surgery. The safety profile of D-MPH is nowwell known and has been established in adults as well as in children,for whom it is the primary therapy for treating ADHD. Also wellunderstood now are its mechanisms of action in the brain which entailblocking of monoaminergic transport systems, thereby increasing thebrain levels of the arousal neurotransmitters dopamine, norepinephrineand histamine. At present, there is no medical indication forintravenous use of D-MPH. Therefore, one aspect of the present inventionrelates to the use of intravenous D-MPH and/or L-MPH to actively reversethe state of general anesthesia.

In some embodiments, a composition comprising D-MPH and/or L-MPH can bewidely used in subjects to rapidly reverse general anesthesia at the endof surgery. In addition, D-MPH may find use as a “rescue” drug inpatients who are accidentally oversedated and become unresponsive orapneic during conscious sedation.

The effective dose of methylphenidate, including D-methylphenidatealone, L-methylphenidate alone, or a mixture of those two, is selectableand variable. For example, the dose may be about 0.5 mg/kg of patientweight. Further, restoration of mobility or consciousness in ananesthetized patient who has been exposed to an effective dosemethylphenidate, including D-methylphenidate alone, Lmethylphenidatealone, or a mixture of those two, may occur quickly. For example, suchrestoration of mobility or consciousness may occur in as little as about5 minutes or about 10 minutes.

Amphetamine and Amphetamine Analogues

One aspect of the present invention relates to use of Amphetamine as ananesthesia-reversing agent according to the compositions and methods asdisclosed herein to rapidly reverse a subject's unconsciousness bygeneral anesthesia, e.g., isoflurane-induced or propofol-inducedanesthesia or other anesthesia's, for example etimidate. In someembodiments, amphetamine is dextro-amphetamine (D-amphetamine) or anypharmaceutically acceptable salts, polymorphs or esters thereof. In someembodiments, amphetamine is levo-amphetamine (L-amphetamine) or anypharmaceutically acceptable salts, polymorphs or esters thereof.

Amphetamine has the Chemical Formula:

Amphetamine prodrugs, and methods of preparing amphetamine prodrugs havebeen described previously. U.S. Pat. No. 7,105,486, which describes thepreparation of lisdexamfetamine, is hereby incorporated by reference atcols. 20 to 22 for its teachings regarding the synthesis of amino acidamphetamine prodrugs. In addition to amino acid prodrugs it is possibleto prepare a number of other amphetamine prodrugs by reacting theamphetamine amino group with a chemically labile moiety. It is withinthe ability of those of ordinary skill in the art of chemical synthesisto prepare carboxamide amphetamine prodrugs by reacting amphetamine withan aliphatic aldehyde and to prepare carbamate amphetamine prodrugs byreacting amphetamine with an aliphatic organic acid.

Lisdexamfetamine dimesylate, CAS Reg. No. 608137-32-3,(25)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamidedimethanesulfonate, is an amphetamine prodrug in which L-lysine iscovalently bound to d-amphetamine. Lisdexamfetamine dimesylate is soldunder the trade name VYVANSE (Shire). It has the chemical formula:

“Lisdexamfetamine” is typically administered as a dimesylate salt butincludes all pharmaceutically acceptable salts of lisdexamfetamine freebase. The term “lisdexamfetamine” also encompasses any pharmaceuticallyacceptable salt, polymorph or ester thereof.

In some embodiments, amphetamine, amphetamine analogues or prodrugsthereof can be used as an anesthetic-reversing agent as disclosed hereinat a dose of about at least about 0.1 mg/kg, or about 0.2 mg/kg, orabout 0.3 mg/kg, or about 0.4 mg/kg, or about 0.5 mg/kg, or about 0.6mg/kg, or about 0.7 mg/kg, or about 0.8 mg/kg or about 0.9 mg/kg, orabout 1 mg/kg, or about 2 mg/kg or about 3 mg/kg or 4 mg/kg or 5 mg/kgor about 6 mg/kg or about 7 mg/kg or about 8 mg/kg or about 9 mg/kg orabout 10 mg/kg, or greater than about 10 mg/kg. In some embodiments,amphetamine, amphetamine analogues or prodrugs thereof can be used as ananesthetic-reversing agent as disclosed herein at a dose of about 0.5mg/kg. In some embodiments, amphetamine, amphetamine analogues orprodrugs thereof can be used as an anesthetic-reversing agent asdisclosed herein at a dose of between 0.1 mg/kg to 0.5 mg/kg, or about0.5-1 mg/kg, or about 1-2 mg/kg or about 2-3 mg/kg, or about 2-5 mg/kgor about 5-10 mg/kg, or about 0.05-5 mg/kg or any integer between 0.5mg/kg and about 10 mg/kg.

Modafinil or any Pharmaceutically Acceptable Salts, Polymorphs or EstersThereof

One aspect of the present invention relates to use of modafinil as ananesthesia-reversing agent according to the compositions and methods asdisclosed herein to rapidly reverse a subject's unconsciousness bygeneral anesthesia, e.g., inhalation anesthesia such as, but not limitedto isoflurane-induced or propofol-induced anesthesia oretomidate-induced anesthesia.

Modafinil is also known by the names PROVIGIL™, ALERTEC™, MODAVIGIL™MODALERT™, MODIODAL™, MODAFINILO™, CARINA™, VIGIA™, and is an analepticdrug manufactured by Cephalon, and is approved by the U.S. Food and DrugAdministration (FDA) for the treatment of narcolepsy, shift work sleepdisorder, and excessive daytime sleepiness associated with obstructivesleep apnea.

Modafinil compound is 2-[(diphenylmethyl)sulfinyl]acetamide and can besynthesized by the method as described in U.S. Pat. No. 4,927,855, whichis incorporated herein by reference, and has the following chemicalformula:

In some embodiments, Modafinil used in the methods and compositions asdisclosed herein as an anesthesia-reversing agent is an acetamidederivative modafinil, which is 2-(benzhydrylsulfinyl)acetamide and isalso known as 2-[(diphenylmethyl)sulfinyl]acetamide. In someembodiments, Modafinil polymeric forms can be used, such as thosedisclosed in U.S. Pat. Nos. 7,649,020; 7,405,323; 6,992,219, as well asenantiomers, analogues and derivatives can be used which are disclosedin U.S. Pat. Nos. 7,704,975; 7,779,540; 7,576,133; 7,566,805; 7,541,493;7,368,591; 7,317,126; 7,316,918; 7,297,346; 7,235,691; 7,229,644;7,141,555; 7,115,281; 7,087,647; 7,057,068; 6,489,363; 6,348,500;6,346,548; 5,612,379; 5,401,776, each of which are incorporated hereinin their entirety by reference.

In some embodiments, modafinil can be used as an anesthetic-reversingagent as disclosed herein at a dose of about at least about 1 mg/kg, orabout 2 mg/kg or about 3 mg/kg or 4 mg/kg or 5 mg/kg or about 10 mg/kgor about 20 mg/kg or greater than about 20 mg/kg. In some embodiments,modafinil can be used as an anesthetic-reversing agent as disclosedherein at a dose of about 5 mg/kg or about 10 mg/kg. In someembodiments, modafinil can be used as an anesthetic-reversing agent asdisclosed herein at a dose of between 0.5 mg/kg and 1 mg/kg, or about1-2 mg/kg or about 2-3 mg/kg, or about 2-5 mg/kg or about 5-10 mg/kg, orabout 10-20 mg/kg or about 0.025-0.5 mg/kg or any integer between 0.025mg/kg and about 20 mg/kg.

Amantadine or any Pharmaceutically Acceptable Salts, Polymorphs orEsters Thereof

One aspect of the present invention relates to use of amantadine as ananesthesia-reversing agent according to the compositions and methods asdisclosed herein to rapidly reverse a subject's unconsciousness bygeneral anesthesia, e.g., inhalation anesthesia such as, but not limitedto isoflurane-induced or propofol-induced anesthesia oretomidate-induced anesthesia.

Amantadine is the organic compound known formally as 1-adamantylamine or1-aminoadamantane. The molecule consists of adamantane backbone that hasan amino group substituted at one of the four methyne positions. Thispharmaceutical is sold under the name SYMMETREL™ for use both as anantiviral and an antiparkinsonian drug. Rimantadine is a closely-relatedderivative of adamantane with similar biological properties. Amantadinehas the following chemical formula:

Extended release forms of amantadine have been described in the art.U.S. Pat. No. 5,358,721, to Guittard et al., and U.S. Pat. No.6,217,905, to Edgren et al., which are incorporated herein in theirentirety by reference, and each disclose an oral osmotic dosage formcomprising an antiviral or anti-Parkinson's drug, respectively, where ineach case amantadine is listed as a possible drug to be utilized in thedosage form. U.S. Pat. No. 6,194,000, to Smith et al., incorporatedherein in their entirety by reference, discloses analgesic immediate andcontrolled release pharmaceutical compositions utilizing NMDA receptorantagonists, such as amantadine, as the active agent. U.S. Patent Appl.Publication Nos. US 2006/0252788, US 2006/0189694, US 2006/0142398, andUS 2008/0227743, incorporated herein in their entirety by reference, allto Went et al., each disclose the administration of an NMDA receptorantagonist, such as amantadine, optionally in controlled release form.U.S. Patent application US 2011/0189273 also incorporated herein in itsentirety by reference, discloses alternative formulations of amantidine.

In some embodiments, amantadine is amantadine hydrochloride isdesignated chemically as 1-adamantanamine hydrochloride or the chemicalstructure:

Amantadine hydrochloride is a stable white or nearly white crystallinepowder freely soluble in water and soluble in alcohol and in chloroform.Amantadine hydrochloride has pharmacological actions as both ananti-Parkinson and an antiviral drug. In some embodiments, Amantadinecan be used as an anesthetic-reversing agent as disclosed herein at adose of about at least about 1 mg/kg, or about 2 mg/kg or about 3 mg/kgor 4 mg/kg or 5 mg/kg or greater than 5 mg/kg. In some embodiments,Amantadine can be used as an anesthetic-reversing agent as disclosedherein at a dose of about 3 mg/kg. In some embodiments, Amantadine canbe used as an anesthetic-reversing agent as disclosed herein at a doseof between 0.5 mg/kg and 1 mg/kg, or about 1-2 mg/kg or about 2-3 mg/kg,or about 2-5 mg/kg or about 0.025-0.5 mg/kg or any integer between 0.025mg/kg and about 10 mg/kg.

Caffeine or any Pharmaceutically Acceptable Salts, Polymorphs or EstersThereof

One aspect of the present invention relates to use of caffeine as ananesthesia-reversing agent according to the compositions and methods asdisclosed herein to rapidly reverse a subject's unconsciousness bygeneral anesthesia, e.g., inhalation anesthesia such as, but not limitedto isoflurane-induced or propofol-induced anesthesia oretomidate-induced anesthesia.

Caffeine, or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione, has thestructural formula as shown below. This substance has been used alone,intravenously, in the treatment of headaches and has also been used incombination with selected drugs. Caffeine has the following structure:

Caffeine is a methylxanthines, and caffeine for use as ananesthesia-reversing agent can be obtained and delivered (e.g., viainhalation routes or aqueous dosage forms or oral spray forms, nasaldelivery methods) according to the methods as disclosed in U.S. Pat.Nos. 7,560,465; 7,448,469; 5,900,416; 5,700,484; 5,502,056; 5,456,677;7,488,469; 7,560,465; 7,078,016; 4,778,810; 4,486,436 each of which areincorporated herein in their entirety by reference.

In some embodiments, caffeine can be used as an anesthetic-reversingagent as disclosed herein at a dose of about at least about 1 mg/kg, orabout 2 mg/kg or about 3 mg/kg or 4 mg/kg or 5 mg/kg or about 6 mg/kg orabout 7 mg/kg or about 8 mg/kg or about 9 mg/kg or about 10 mg/kg, orgreater than about 10 mg/kg. In some embodiments, caffeine can be usedas an anesthetic-reversing agent as disclosed herein at a dose of about5 mg/kg. In some embodiments, caffeine can be used as ananesthetic-reversing agent as disclosed herein at a dose of between 0.5mg/kg and 1 mg/kg, or about 1-2 mg/kg or about 2-3 mg/kg, or about 2-5mg/kg or about 5-10 mg/kg, or about 0.05-5 mg/kg or any integer between0.5 mg/kg and about 10 mg/kg.

Anesthesia-Reversing Agents

In particular, the present invention generally relates to increasing thetime to consciousness after withdrawal of anesthesia using a compositioncomprising at least one anesthesia-reversing agent as disclosed herein,wherein the anesthesia-reversing agent is selected from the groupcomprising; methylphenidate (MPH), amphetamine, modafinil, amantadine,caffeine, or analogues or derivatives thereof.

In some embodiments, an anesthesia-reversing agent is MPH, e.g., D-MPHor any pharmaceutically acceptable salt, polymorph or ester thereof.

In some embodiments, a composition comprising at least oneanesthesia-reversing agent as disclosed herein is administered in aneffective amount to facilitate emergence of general anesthesia-inducedunconsciousness in a subject, or decrease the time to cognitive functionafter general anesthesia of a subject by a statistically significantincrease as compared to in the absence of an anesthesia-reversing agent.In some embodiments, a composition comprising at least oneanesthesia-reversing agent as disclosed herein is administered to anunconscious subject intravenously almost immediately afteradministration of the general anesthesia is removed or stopped, todecrease the time to consciousness by a statistically significantincrease as compared to in the presence of a control agent, such as, forexample, physotigamine (PHY).

In some embodiments, a composition comprising at least oneanesthesia-reversing agent as disclosed herein, for example, any one, orany combination of a methylphenidate (MPH), amphetamine, modafinil,amantadine, caffeine, or analogues or derivatives thereof, or inparticular, D-MPH is administered in an effective amount to a subject toreduce the time to consciousness (e.g., time to awakening) by at leastabout 10%, or at least about 20%, or at least about 30%, or at leastabout 40%, or at least about 50%, or at least about 60%, or at leastabout 70%, or at least about 80%, or at least about 90%, or at leastabout 100%, or more than 100%, for example, at least about 2-fold, or atleast about 3-fold, or at least about 4-fold, or at least about 5-fold,or at least about 6-fold, or at least about 7-fold, or at least about8-fold, or at least about 9-fold, or at least about 10-fold, or morethan 10-fold as compared to the time for passive awakening from generalanesthesia-induced unconsciousness, or compared to awakening fromgeneral anesthesia-induced unconsciousness in the presence of a negativecontrol agent, such PHY.

In some embodiments, a composition comprising at least oneanesthesia-reversing agent as disclosed herein, for example, any one, orany combination of a methylphenidate (MPH), amphetamine, modafinil,amantadine, caffeine, or analogues or derivatives thereof, or inparticular, D-MPH is administered in an effective amount to a subject sothat the subject awakens or emerges from general-anesthesia inducedunconsciousness earlier (or faster) by at least about 10%, or at leastabout 20%, or at least about 30%, or at least about 40%, or at leastabout 50%, or at least about 60%, or at least about 70%, or at leastabout 80%, or at least about 90%, or at least about 100%, or more than100%, for example, at least about 2-fold, or at least about 3-fold, orat least about 4-fold, or at least about 5-fold, or at least about6-fold, or at least about 7-fold, or at least about 8-fold, or at leastabout 9-fold, or at least about 10-fold, or more than 10-fold ascompared to the time required for passive awakening from generalanesthesia-induced unconsciousness, or compared to awakening fromgeneral anesthesia-induced unconsciousness in the presence of a negativecontrol agent, such PHY.

In some embodiments, a composition comprising at least oneanesthesia-reversing agent as disclosed herein, for example, any one, orany combination of a methylphenidate (MPH), amphetamine, modafinil,amantadine, caffeine, or analogues or derivatives thereof, or inparticular, D-MPH is administered in an effective amount to a subject toreduce symptoms of delirium on awakening or emergence fromgeneral-anesthesia induced unconsciousness by at least about 10%, or atleast about 20%, or at least about 30%, or at least about 40%, or atleast about 50%, or at least about 60%, or at least about 70%, or atleast about 80%, or at least about 90%, or at least about 100%, or morethan 100%, for example, at least about 2-fold, or at least about 3-fold,or at least about 4-fold, or at least about 5-fold, or at least about6-fold, or at least about 7-fold, or at least about 8-fold, or at leastabout 9-fold, or at least about 10-fold, or more than 10-fold ascompared to the delirium symptoms experienced by subject on passiveawakening from general anesthesia-induced unconsciousness, or comparedto awakening from general anesthesia-induced unconsciousness in thepresence of a negative control agent, such PHY. The reduced delirium bythe compositions and methods as disclosed herein can be emergencedelirium and hypoactive emergence delirium, which are well know bypersons of ordinary skill in the art, and are described in Radtke etal., Minerva Anestesiol. 2010; 76(6):394-403. Delirium is disturbance ofconsciousness, and a change in cognition or a perception of a mentaldissociation that can include hallucinations, psychimotor agitation anddelusions, and can include restlessness, incoherence, irritability,screaming and involuntary activity, as well as belligerent behavior anddisorientation. Delerium can be quantitated using the Rikersedation-agitated scale (Lepouse et al., Emergence Delirium In Adults inthe Post-Anesthesia Care Unit, J. Anesthesia, 2006; 96; 747-753), andincludes assessment of eye contact, purposeful actions, awareness ofsurroundings, restlessness and inconsolability and the like.

In some embodiments, a subject is a mammal. In certain embodiments, amammal is an animal. In certain embodiments, the mammal is a human. Insome embodiments, the human is a child. In certain embodiments, a humanis under the age of 18. In some embodiments, a human is under the age of10. In some embodiments, a human is under the age of 2. In someembodiments, an animal is a domesticated animal, including but notlimited to, dog, cat, horse, cattle and the like.

In some embodiments, provided herein are methods for increasing theamount of consciousness or mental cognitive functioning of anunconscious subject wherein the subject is unconscious by generalanesthesia, comprising administering to the subject a compositioncomprising one or more anesthesia-reversing agent selected from thegroup comprising; methylphenidate (MPH), amphetamine, modafinil,amantadine, caffeine, or analogues or derivatives thereof, as the freeacid, a pharmaceutically acceptable salt, or ester thereof.

In some embodiments, the anesthesia-reversing agent is administered tothe subject after administration of the general anesthesia, and in someembodiments, the anesthesia-reversing agent is administered in the last10% of the surgery, concurrent with the administration of the generalanesthesia. In such latter embodiments, it is envisioned that the doseof the general anesthesia is reduced as the dose of theanesthesia-reversing agent is increased, such that there is an inverserelationship between the dose of the general anesthesia and the dose ofthe anesthesia-reversing agent.

In some embodiments, the methods for emerging a subject from generalanesthesia-induced-unconsciousness further comprises administering tothe subject at least one other therapeutic agent with at least one otheranesthesia reversing agent, wherein the therapeutic agent can beselected from the group consisting of; analgesic, pain medication,anti-inflammatory agent and the like.

In one embodiment, the invention relates to compositions and methodsuseful in the treatment and prevention of delirium occurring duringemergence of general-anesthesia-induced unconsciousness. Delirium asused herein refers to a disturbance of consciousness, and a change incognition or a perception of the subject as they awaken from generalanesthesia-induced unconsciousness that can include hallucinations,psychimotor agitation and delusions, and can include restlessness,incoherence, irritability, screaming and involuntary activity, as wellas belligerent behavior and disorientation. Delerium can be quantitatedusing the Riker sedation-agitated scale (Lepouse et al., EmergenceDelirium In Adults in the Post-Anesthesia Care Unit, J. Anesthesia,2006; 96; 747-753), and includes assessment of eye contact, purposefulactions, awareness of surroundings, restlessness and inconsolability andthe like. Delerium can be measured by one of ordinary skill in the artby the Riker sedation-agitated scale.

Without wishing to be bound by theory, emergence delirium (ED) is alsoreferred to in the art as emergence agitation (EA), and is a welldocumented phenomenon occurring in children and adults in the immediatepostoperative period. Delirium is disturbance of consciousness, and achange in cognition or a perception of a mental dissociation that caninclude hallucinations, psychimotor agitation and delusions, and caninclude restlessness, incoherence, irritability, screaming andinvoluntary activity, as well as belligerent behavior anddisorientation. Delerium can be quantitated using the Rikersedation-agitated scale (Lepouse et al., Emergence Delirium In Adults inthe Post-Anesthesia Care Unit, J. Anesthesia, 2006; 96; 747-753), andincludes assessment of eye contact, purposeful actions, awareness ofsurroundings, restlessness and inconsolability and the like. Inchildren, emergence delirium is defined as a dissociated state ofconsciousness in which the child is inconsolable, irritable,uncompromising or uncooperative, typically thrashing, crying, moaning,or incoherent. Additionally paranoid ideation has been observed incombination with these emergence behaviors. Characteristically thesechildren do not recognize or identify familiar and known objects orpeople. Parents who witness this state claim the behavior is unusual anduncustomary for the child. Although generally self limiting (5-15 min)ED can be severe and may result in physical harm to the child andparticularly the site of surgery.

Signs and symptoms of emergence delirium or agitation after anesthesiainclude excitement and alternating periods of lethargy followed byexcitement and disorientation. Inappropriate behavior such as screaming,kicking, and use of profanities also may occur. Also, the patientsgenerally do not respond appropriately to commands.

Emergence delirium can occur after most inhalational agents, e.g.,inhalation anesthesia agents desflurane and sevoflurane and intravenousagents including midazolam, remifentanil and propofol. Other drugs knowto be associated with ED include 1) atropine or scopolamine, 2)ketamine, 3) droperidol, 4) barbiturates and possibly, 5)benzodiazepines.

Physiological causes of emergence delirium include, but are not limitedto, age, Hypoxemia, Hypercapnia, Hyponatremia, Hypoglycemia,Intracranial injury, Sepsis, Alcohol withdrawal, Airway obstruction,Gastric dilatation, Full bladder, Pain, Hypothermia, Sensory overload,and Sensory deprivation and electrolyte disturbances. Pharmacologicalcauses of emergence delirium include, but are not limited to rapidemergence, Ketamine, Droperidol, Benzodiazepines, Metoclopramide,Atropine, Scopolamine, volitle anestheics, raglan, centralanticholinergic syndrome, neuroleptics, digoxin, beta-blockers,steroids, anticonvulsants, oral hypoglycemics.

Risk factors for emergence delirium are well known, and include, withoutlimitation, age, (e.g., ages 2-5 are most vulnerable), underlyingmedical condition, medication, CNS disorders, electrolyte disturbances,temperament, surgery type and anesthesia type. Adverse effects of ED:risk of injury to patient and staff, worry of permanent neurologicalsequelae, disruptive to the post-anesthesia care unit, displeasure ofthe subject, family and staff with the whole operative experience

Administration

In some embodiments, compositions comprising at least one or anycombination of anesthesia-reversing agent selected from the groupcomprising; methylphenidate (MPH), amphetamine, modafinil, amantadine,caffeine, or analogues or derivatives thereof, in particular D-MPH whichcan be directly or indirectly administered to the patient. Indirectadministration can also be performed, for example, by administering tothe subject a pro-drug of the anesthesia-reversing agent andsubsequently introducing to the subject an activator of the prodrug torelease the activated functional anesthesia-reversing agent to thepatient.

Direct administration of compositions comprising at least one or anycombination of anesthesia-reversing agent selected from the groupcomprising; methylphenidate (MPH), amphetamine, modafinil, amantadine,caffeine, or analogues or derivatives thereof, can also be by oral,parenteral, sublingual, rectal such as suppository or enteraladministration, or by pulmonary absorption or topical application.Parenteral administration may be by intravenous injection, subcutaneousinjection, intramuscular injection, intra-arterial injection,intrathecal injection, intra peritoneal injection or direct injection orother administration to one or more specific sites. Injectable forms ofadministration are sometimes preferred for maximal effect in, forexample, bone marrow. When long term administration by injection isnecessary, venous access devices such as medi-ports, in-dwellingcatheters, or automatic pumping mechanisms are also preferred whereindirect and immediate access is provided to the arteries in and aroundthe heart and other major organs and organ systems.

In some embodiments, the anesthesia-reversing agent selected from thegroup comprising; methylphenidate (MPH), amphetamine, modafinil,amantadine, caffeine, or analogues or derivatives thereof, isadministered via intravenous administration.

In some embodiments, a composition comprising at least one or anycombination of anesthesia-reversing agent selected from the groupcomprising; methylphenidate (MPH), amphetamine, modafinil, amantadine,caffeine, or analogues or derivatives thereof can be administered bytransdermal transfusion such as with a dermal or cutaneous patch, bydirect contact with a particular tissue, for example, bone marrowthrough an incision or some other artificial opening into the body.

In some embodiments, compositions may also be administered byinhalation, e.g., via a aerosol administration or to the nasal passagesas a spray. Arteries of the nasal area provide a rapid and efficientaccess to the bloodstream and immediate access to the pulmonary system.Access to the gastrointestinal tract, which can also rapidly introducesubstances to the blood stream, can be gained using oral, enema, orinjectable forms of administration. Compositions may be administered asa bolus injection or spray, can in some embodiments can be administeredas a bolus injection immediately after surgery and then sequentiallyover time (episodically) such as every two, four, six or eight hours,every day (QD) or every other day (QOD), or over longer periods of timesuch as weeks to months. In some embodiments, compositions comprising ananesthesia-reversing agent can also be administered in a timed-releasefashion such as by using slow-release resins and other timed or delayedrelease materials and devices.

Orally active compositions comprising at least one or any combination ofanesthesia-reversing agent selected from the group comprising;methylphenidate (MPH), amphetamine, modafinil, amantadine, caffeine, oranalogues or derivatives thereof, in D-MPH are more preferred as oraladministration is usually the safest, most convenient and economicalmode of drug delivery. Oral administration is usually disadvantageousbecause compositions are poorly absorbed through the gastrointestinallining Compounds which are poorly absorbed tend to be highly polar.Consequently, the anesthesia-reversing agents as described herein can bemade orally bioavailable by reducing or eliminating their polarity. Thiscan often be accomplished by formulating a composition with acomplimentary reagent which neutralizes its polarity, or by modifyingthe compound with a neutralizing chemical group. Oral bioavailability isalso a problem because drugs are exposed to the extremes of gastric pHand gastric enzymes. These problems can be overcome in a similar mannerby modifying the molecular structure to withstand very low pH conditionsand resist the enzymes of the gastric mucosa such as by neutralizing anionic group, by covalently bonding an ionic interaction, or bystabilizing or removing a disulfide bond or other relatively labilebond.

Treatments to the subject may be therapeutic or prophylactic. Bothprophylactic and therapeutic uses are readily acceptable because thesecompounds are generally safe and non-toxic. In some embodiments,prophylactic treatments involve administration of a compositioncomprising an anesthesia-reversing agent selected from the groupcomprising; methylphenidate (MPH), amphetamine, modafinil, amantadine,caffeine, or analogues or derivatives thereof to reverse generalanesthesia in a subject when unconsciousness is no longer desired and toprevent the delirium on awakening from anesthesia-inducedunconsciousness. This is particularly useful for all subjects, asemergence delirium is a serious clinical problem with an incidence of ashigh as 30% in pediatric patients undergoing general anesthesia.

Prophylactic treatment is also useful when the subject has priorincidence of delirium on emergence from general anesthesia-inducedunconsciousness, or is a subject suspected to experience delirium onemergence from general anesthesia-induced unconsciousness without havingany prior delirium symptoms on anesthesia. For example, otherwisehealthy patients who have at least one or more of the characteristics ofrisk of delirium can be administered a composition comprising at leastone anesthesia-reversing agent as disclosed herein prophylactically.Subjects at risk of delirium include any subject undergoing generalanesthesia with one or more of the following, between 2-7 years of age,Hypoxemia, Hypercapnia, Hyponatremia, Hypoglycemia, Intracranial injury,Sepsis, Alcohol withdrawal, Airway obstruction, Gastric dilatation, Fullbladder, Pain, Hypothermia, Sensory overload, and Sensory deprivationand electrolyte disturbances. Subjects at risk of delirium also includeany subject undergoing general anesthesia currently one or moremedications such as, Ketamine, Droperidol, Benzodiazepines,Metoclopramide, Atropine, Scopolamine, volatile anesthetics, raglan,central anticholinergic syndrome, neuroleptics, digoxin, beta-blockers,steroids, anticonvulsants, oral hypoglycemics. Subjects at risk ofdelirium on emergence of general-anesthesia-induced unconsciousnesswithout limitation, age, (e.g., ages 2-5 are most vulnerable),underlying medical condition, medication, CNS disorders, electrolytedisturbances, temperament, surgery type and anesthesia type.

In some embodiments, therapeutic treatment involves administration ofone or more anesthesia-reversing agent as disclosed herein to a subjectsuffering from one or more symptoms of the anesthesia-induced deliriumupon awakening. Symptoms of delirium are commonly known to ordinarysurgery practitioners (physicians, nurses, anesthesia physicians andtechnicians) and typically include, for example, inconsolable,irritable, uncompromising or uncooperative, typically thrashing, crying,moaning, incoherent, paranoid, inability to recognize or identifyfamiliar or known objects or people, excitement and alternating periodsof lethargy followed by excitement and disorientation, as well asinappropriate behavior such as screaming, kicking, and use ofprofanities also may occur. The present invention of administeringanesthesia-reversing agents provides relief and even partial relief fromone or more of these symptoms. Further, treatments that alleviate apathological symptom can allow for other treatments to be administered.

In some embodiments, therapeutic treatment of a subject with ananesthesia-reversing agent as disclosed herein can be administered to anunconscious subject whom are inadvertently or accidently oversedated. Insome embodiments, therapeutic treatment of a subject with ananesthesia-reversing agent as disclosed herein can be used for a subjectwhom has become unresponsive or apnic during conscious sedation as aresult of the general anesthesia.

In some embodiments, composition comprising an anesthesia-reversingagent selected from the group comprising; methylphenidate (MPH),amphetamine, modafinil, amantadine, caffeine, or analogues orderivatives thereof as disclosed herein can be used in combination withother anti-delirium agents or therapies to maximize the effect of thecompositions in an additive or synergistic manner. Anti-delirium agentsinclude, without limitation, midazolam, benzodizepines, dexmedetomidineand clonidine, opiods and other agents. Combinations of therapies mayalso be effective in any one of an additive, logarithmic, orsynergistic, and methods involving combinations of therapies may besimultaneous protocols, intermittent protocols or protocols which areempirically determined.

Doses and Administration:

In some embodiments, a composition comprising an anesthesia-reversingagent selected from the group comprising; methylphenidate (MPH),amphetamine, modafinil, amantadine, caffeine, or analogues orderivatives thereof can be administered to the subject by pulsedadministration which can be more effective than continuous treatmentbecause total pulsed doses are often lower than would be expected fromcontinuous administration of the same composition. Each pulse dose canbe reduced and the total amount of drug administered over the course oftreatment is minimized.

In traditional forms of therapy, repeated administration is designed tomaintain a desired level of an active ingredient in the body. Veryoften, complications that develop can be attributed to dosage levelsthat, to be effective, are near toxic or otherwise harmful to normalcells. In contrast, with pulse therapy, in vivo levels of drug dropbelow that level required for effective continuous treatment. Therefore,pulsing is not simply the administration of a sufficiently large bolussuch that there will be therapeutically sufficient amount of ananesthesia-reversing agent available for the required period of time foreffective awakening after anthestisa-induced unconsciousness. Pulsedadministration can substantially reduce the amount of the compositionadministered to the patient per dose or per total treatment regimen withan increased effectiveness. This represents a significant saving intime, effort and expense and, more importantly, a lower effective dosesubstantially lessens the number and severity of complications that maybe experienced by the patients.

Individual pulses of a composition comprising an anesthesia-reversingagent selected from the group comprising; methylphenidate (MPH),amphetamine, modafinil, amantadine, caffeine, or analogues orderivatives thereof as disclosed herein can be delivered to the patientcontinuously over a period of several minutes, such as about 2-10,10-15, 15-20, 20-25, 25-30, 30-40, 40-50 or 50-60 minutes, or severalhours, such as 1-2, 3, 4, 5, 6, 7, 8-10, or 10-12 hours, preferably fromabout 30 minutes to about 12 hours and more preferably from about 30minutes to about 2 hours. Alternatively, periodic doses can beadministered in a single bolus or a small number of injections of thecomposition over a short period of time, typically less than 1 or 2hours. In certain instances, a subject can stop receiving the pulses ofa composition comprising an anesthesia-reversing agent when the subjectis substantially awake and is mobile following generalanesthesia-induced unconsciousness, such that there are positiveconsequences that raise the patient's standard of post-operative caresuch as, for example, increased activity or mobility, fewer anesthesiarelated side-effects, quicker hospital stay post-surgery etc.

The interval between pulses or the interval of no delivery is greaterthan 12 hours, and can be shorter, e.g., every 10 minutes, or every 15minutes, or every 30 minutes till the subject is fully conscious aftergeneral-anesthesia induced unconsciousness. Often, the interval betweenpulses can be calculated by administering another dose of thecomposition when the composition or the active component of thecomposition is no longer detectable in the patient prior to delivery ofthe next pulse. Intervals can also be calculated from the in vivohalf-life of the composition. Intervals may be calculated as greaterthan the in vivo half-life, or 2, 3, 4, 5 and even 10 times greater thecomposition half-life. For compositions with fairly rapid half lives,intervals may be 25, 50, 100, 150, 200, 250 300 and even 500 times thehalf life of the chemical composition. The number of pulses in a singletherapeutic regimen may be as little as two, but is typically from about5 to 10, 10 to 20, 15 to 30 or more. In some embodiments, patientsreceive the anesthesia-reversing agent till the subject is fullyconscious and mobile and cognitive function restored according to themethods of this invention without the problems (e.g., delirium) andinconveniences associated with emergence or awakening from generalanesthesia-induced unconsciousness passively or without ananesthesia-reversing agent as disclosed herein.

In certain embodiments, a composition comprising an anesthesia-reversingagent selected from the group comprising; methylphenidate (MPH),amphetamine, modafinil, amantadine, caffeine, or analogues orderivatives thereof as disclosed herein are administered by most anymeans, but are preferable delivered to the patient as an injection (e.g.intravenous, subcutaneous, intraarterial), infusion or instillation, andmore preferably by oral ingestion.

Pulsed administration of one or more pharmaceutical compositionscomprising a HbF-inducing agent can be used for prophylactic treatment,e.g., for example, a subject who will, or has or is currently undergoinggeneral anesthesia. In some embodiments, pulsed administration can bemore effective than continuous treatment as pulsed doses results in theuse of an overall lower amount of an anesthesia-reversing agent thanwould be expected from continuous administration of the samecomposition. Each pulse dose can be reduced and the total amount of drugadministered over the course of treatment to the subject can beminimized. Pulsed administration can provide a saving in time, effortand expense and a lower effective dose can lessen the number andseverity of complications that can be experienced by a subject. As such,pulsing can be more effective than continuous administration of the samecomposition.

In some embodiments, the number of pulses in a single therapeuticregimen can be as little as two, but can be from about 5 to 10, 10 to20, 15 to 30 or more. Compositions can be administered by most anymeans, and can be delivered to the subject as an oral formulation, orinjection (e.g. intravenous, subcutaneous, intraarterial), infusion orinstillation. Various methods and apparatus for pulsing compositions byinfusion or other forms of delivery to the patient are disclosed in U.S.Pat. Nos. 4,747,825; 4,723,958; 4,948,592; 4,965,251 and 5,403,590,which are incorporated herein in their entirety by reference.

In some embodiments, a composition comprising an anesthesia-reversingagent as disclosed herein can be co-administered to a subjectconcurrently with another agent or treatment regimen, e.g., concurrentlyat the end of surgery with pain medication or during the withdrawal ofthe anesthesia agent. In some embodiments, a composition comprising ananesthesia-reversing agent can be co-administered with a pharmaceuticalcomposition comprising an comprising one or more addition agents. Thepharmaceutical compositions can also be provided by pulsedadministration, concurrently with the anesthesia-reversing agent, or inthe periods inbetween the pulse-administration of theanesthesia-reversing agent (e.g., intermittently with theanesthesia-reversing agent). For example, a composition comprising ananesthesia-reversing agent can be administered to a subject, followed bya pain relieving agent after an interval of time has passed, and thisorder of administration the same or similar time interval can berepeated, for example, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or moretimes.

Pharmaceutical Compositions and Preparations

In some embodiments, a pharmaceutical composition comprising ananesthesia-reversing agent as disclosed herein administered according toa method of the invention can be administered intravenously or orally ineffective dosages, depending upon the weight, body surface area, andcondition of the subject being treated. In some instances, variationsoccur depending upon the species of the subject being treated and itsindividual response to said anesthesia agent or anesthesia-reversingagent as disclosed, as well as on the type of an anesthesia-reversingagent chosen and the time period and interval at which suchadministration of the anesthesia-reversing agent as disclosed herein iscarried out with respect of stopping the administration of the generalanesthesia.

In some embodiments, the administration of the pharmaceuticalcomposition comprising an anesthesia-reversing agent as disclosed hereinaccording to a method of the invention is carried out in single ormultiple doses. For example, the composition can be administered in awide variety of different dosage forms, i.e., it may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, dragees, capsules, lozenges, troches, hard candies, aqueoussuspensions, elixirs, syrups, and the like. Such carriers include soliddiluents or fillers, sterile aqueous media and various non-toxic organicsolvents, etc. Moreover, oral pharmaceutical compositions can besuitably sweetened and/or flavored.

In certain embodiments, pharmaceutical compositions comprising ananesthesia-reversing agent as disclosed herein are suitable forintravenous or oral administration. Suitable pharmaceutical compositionsfor oral administration can be in the form of capsules, tablets, pills,lozenges, cachets, dragees, powders, granules; or as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-water orwater-in-oil liquid emulsion; or as an elixir or syrup; and the like;each containing a predetermined amount of a compound of the presentinvention as an active ingredient. When intended for oral administrationin a solid dosage form (i.e., as capsules, tablets, pills and the like),the pharmaceutical compositions of the invention will typically comprisea compound of the present invention as the active ingredient and one ormore pharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate. Optionally or alternatively, such solid dosageforms may also comprise: filters or extenders, such as starches,microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/orsilicic acid; binders, such as carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, suchas glycerol; disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and/or sodium carbonate; solution retarding agents, such as paraffin;absorption accelerators, such as quaternary ammonium compounds; wettingagents, such as cetyl alcohol and/or glycerol monostearate; absorbents,such as kaolin and/or bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Solid compositions of a similar type may also be employed as fillers ingelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient may be combined with varioussweetening or flavoring agents, coloring matter or dyes, and, if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouslike combinations thereof.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants can also be presentin the pharmaceutical compositions of the invention. Examples ofpharmaceutically-acceptable antioxidants include: water-solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodiumbisulfate, sodium metabisulfate sodium sulfite and the like; oil-solubleantioxidants, such as ascorbyl palmitate, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate,alpha-tocopherol, and the like; and metal-chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like. Coating agents for tablets,capsules, pills and like, include those used for enteric coatings, suchas cellulose acetate phthalate (CAP), polyvinyl acetate phthalate(PVAP), hydroxypropyl methylcellulose phthalate, methacrylicacid-methacrylic acid ester copolymers, cellulose acetate trimellitate(CAT), carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and the like.

In addition, the pharmaceutical compositions of the present inventionmay optionally contain opacifying agents and may be formulated so thatthey release the active ingredient only, or preferentially, in a certainportion of the gastrointestinal tract, optionally, in a delayed manner.Examples of embedding compositions which can be used include polymericsubstances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

If desired, pharmaceutical compositions of the present invention mayalso be formulated to provide slow or controlled release of the activeingredient using, by way of example, hydroxypropyl methyl cellulose invarying proportions; or other polymer matrices, liposomes and/ormicrospheres. Sustained release compositions can be formulated includingthose wherein the active component is derivatized with differentiallydegradable coatings, e.g., by microencapsulation, multiple coatings,etc.

It will be appreciated that the actual preferred amounts of activecompounds used in a given therapy will vary according to the particularcompositions formulated. Optimal administration rates for a givenprotocol of administration can be readily ascertained by those skilledin the art using conventional dosage determination tests conducted withregard to the foregoing guidelines.

It will also be understood that normal, conventionally known precautionswill be taken regarding the administration of compositions comprising ananesthesia-reversing agent as disclosed herein generally to ensure theirefficacy under normal use circumstances. Especially when employed fortreatment of humans and animals in vivo, the practitioner should takeall sensible precautions to avoid conventionally known contradictionsand toxic effects.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. This aspect of the invention willbe readily apparent to those skilled in the art. See, e.g., Remington'sPharmaceutical Sciences (1990) 18th ed., Mack Publishing, Eastern Pa.

In certain embodiments, the pharmaceutical compositions of the inventionis packaged in a unit dosage form. The term “unit dosage form” or “unitdose” refers to a physically discrete unit suitable for dosing a subjecte.g., a patient, i.e., each unit containing a predetermined quantity ofactive agent calculated to produce the desired therapeutic effect eitheralone or in combination with one or more additional units. For example,such unit dosage forms may be capsules, tablets, pills, and the like.Unit doses can also be prepared to contain any useful amount of anactive ingredient (e.g., an anesthesia-reversing agent). For example, aunit dose can be formulated for about a 5 mg/kg dose, or about a 10mg/kg dose or about less than 5 mg/kg dose, for example, between a 0.1mg/kg and 5 mg/kg done, and a unit dose can be, for example, but notlimited to, about 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570mg, 580 mg, 590 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 750 mg, 800mg, 850 mg, 900 mg, 950 mg, 1000 mg, or more than 1000 mg of ananesthesia-reversing agent as disclosed herein per unit dose. Milligramsper dose can refer to either the free acid form of ananesthesia-reversing agent as disclosed herein, or ananesthesia-reversing agent as disclosed herein in a salt or ester form.

Dosing regimens of an anesthesia-reversing agent as disclosed herein canbe tailored to an individual patient, based on any number of clinicallyrelevant parameters including, but not limited to toxicity, tolerance,side-effects, effectiveness, etc.

Combination Therapy

In certain embodiments, a pharmaceutical composition comprising ananesthesia-reversing agent as disclosed herein can be administered aloneor in combination with other known compositions administered to asubject, e.g., a mammal emerging or awakening subject from generalanesthesia-induced unconsciousness. In some embodiments, mammals includecats, dogs, pigs, horses, cows, rats, mice, monkeys, chimpanzees,baboons, and humans. In specific embodiments, the mammal is a human. Insome embodiments, the human is a child. In certain embodiments, thehuman is under the age of 18. In some embodiments, the human is underthe age of 10. In some embodiments, the human is under between the ageof 2-7. In embodiments, the subject is under the age of 2. In oneembodiment, the subject is at risk of developing emergence delirium, orlikely to experience delirium from emergence of general-anesthesiaunconsciousness.

The language “in combination with” a known composition is intended toinclude simultaneous administration of the composition of the inventionand the known composition, administration of the composition of theinvention first, followed by the known composition and administration ofthe known composition first, followed by the composition comprising ananesthesia-reversing agent as disclosed herein.

In some embodiments, in addition to the use of an anesthesia-reversingagent as disclosed herein to facilitate awakening fromgeneral-anesthesia unconsciousness, concurrent administration of otherpharmaceutical and/or nutraceutical compounds can occur. For example,persons can be administered opioids or analgesics (for pain management),and/or antibiotics (for treating secondary infections), andanti-inflammatory agents (to prevent inflammation after surgery). Incertain instances, concurrent treatment with an anesthesia-reversingagent as disclosed herein and a second agent occurs at the same time, oron different regimen schedules. In some embodiments ananesthesia-reversing agent as disclosed herein is an orallybio-available compound that is active at well tolerated doses.

Administration of the compositions comprising an anesthesia-reversingagent as disclosed herein may be by oral, parenteral, sublingual,rectal, or enteral administration, or pulmonary absorption or topicalapplication. Compositions can be directly or indirectly administered tothe patient.

The compositions comprising an anesthesia-reversing agent as disclosedherein can be purchased commercially and prepared as a mixed compositionusing techniques well-known to those of ordinary skill in the art.

Direct administration of a composition comprising ananesthesia-reversing agent as disclosed herein to a subject can be byoral, parenteral, sublingual, rectal such as suppository or enteraladministration, or by pulmonary absorption or topical application.Parenteral administration may be by intravenous (IV) injection,subcutaneous (s.c.) injection, intramuscular (i.m) injection,intra-arterial injection, intrathecal (i.t.) injection, intra-peritoneal(i.p) injection, or direct injection or other administration to thesubject.

Alternatively, pharmaceutical compositions comprising ananesthesia-reversing agent as disclosed herein and/or salts thereof cancontain pharmaceutically-acceptable carriers and other ingredients knownto facilitate administration and/or enhance uptake (e.g., saline,dimethyl sulfoxide, lipid, polymer, affinity-based cellspecific-targeting systems). In some embodiments, a compositioncomprising an anesthesia-reversing agent as disclosed herein and/orsalts thereof can be incorporated in a gel, sponge, or other permeablematrix (e.g., formed as pellets or a disk) and placed in proximity tothe endothelium for sustained, local release. In some embodiments, acomposition comprising an anesthesia-reversing agent as disclosed hereinand/or salts thereof can be administered in a single dose or in multipledoses (e.g., pulses as discussed infra) which are administered atdifferent times.

Pharmaceutical compositions comprising an anesthesia-reversing agent asdisclosed herein and/or salts thereof can be administered by any knownroute. By way of example, a composition comprising ananesthesia-reversing agent as disclosed herein and/or salts thereof canbe administered by a mucosal, pulmonary, topical, or other localized orsystemic route (e.g., enteral and parenteral). The phrases “parenteraladministration” and “administered parenterally” as used herein meansmodes of administration other than enteral and topical administration,usually by injection, and includes, without limitation, intravenous,intramuscular, intraarterial, intrathecal, intraventricular,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular,subarachnoid, intraspinal, intracerebro spinal, and intrasternalinjection, infusion and other injection or infusion techniques, withoutlimitation. The phrases “systemic administration,” “administeredsystemically”, “peripheral administration” and “administeredperipherally” as used herein mean the administration of the agents asdisclosed herein such that it enters the animal's system and, thus, issubject to metabolism and other like processes, for example,subcutaneous administration.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting the subject agents fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation, for example the carrierdoes not decrease the impact of the agent on the treatment. In otherwords, a carrier is pharmaceutically inert.

Suitable choices in amounts and timing of doses, formulation, and routesof administration of a composition comprising an anesthesia-reversingagent as disclosed herein and/or salts thereof can be made with thegoals of achieving a favorable response (e.g., quick awakening withoutdelirium) in the subject who is to emerge from generalanesthesia-induced unconsciousness, and avoiding undue toxicity or otherharm thereto (i.e., safety). Therefore, “effective” refers to suchchoices that involve routine manipulation of conditions to achieve adesired effect.

A bolus of the formulation of a composition comprising ananesthesia-reversing agent as disclosed herein and/or salts thereofadministered to an individual over a short time after (e.g., immediatelyafter), or immediately before the cessation or stopping of theadministration of the anesthesia agent at an appropriate dosingschedule. Alternatively, the effective dose of an anesthesia-reversingagent as disclosed herein can be divided into multiple doses forpurposes of administration, for example, two to twelve doses, or morethan 12-doses during the awakening period of the subject from thegeneral anesthesia-induced unconsciousness. Dosage levels of activeingredients in a pharmaceutical composition comprising ananesthesia-reversing agent as disclosed herein and/or salts thereof canalso be varied so as to achieve a transient or sustained concentrationof the compound or derivative thereof in an individual, especially inand around the blood circulation and to result in the desiredtherapeutic response or protection. But it is also within the skill ofthe art to start doses at levels lower than required to achieve thedesired therapeutic effect and to gradually increase the dosage untilthe desired effect is achieved.

In some embodiments, the amount of a composition comprising ananesthesia-reversing agent as disclosed herein and/or salts thereof canbe administered is dependent upon factors known to a person skilled inthe art such as bioactivity and bioavailability of the compound (e.g.,half-life in the body, stability, and metabolism); chemical propertiesof the compound (e.g., molecular weight, hydrophobicity, andsolubility); route and scheduling of administration, and the like. Itwill also be understood that the specific dose level to be achieved forany particular individual can depend on a variety of factors, includingage, gender, health, medical history, weight, combination with one ormore other drugs, and severity of disease.

Production of compounds comprising an anesthesia-reversing agent asdisclosed herein and/or salts thereof according to present regulationswill be regulated for good laboratory practices (GLP) and goodmanufacturing practices (GMP) by governmental agencies (e.g., U.S. Foodand Drug Administration). This requires accurate and complete recordkeeping, as well as monitoring of QA/QC. Oversight of patient protocolsby agencies and institutional panels is also envisioned to ensure thatinformed consent is obtained; safety, bioactivity, appropriate dosage,and efficacy of products are studied in phases; results arestatistically significant; and ethical guidelines are followed. Similaroversight of protocols using animal models, as well as the use of toxicchemicals, and compliance with regulations is required.

Dosages, formulations, dosage volumes, regimens, and methods foranalyzing results aimed at reducing delirium and/or decreasing time toconsciousness and functional can vary. Thus, minimum and maximumeffective dosages vary depending on the method of administration. Gainof consciousness after anesthesia in a subject can occur within aspecific dosage range, which varies depending on, for example, the race,sex, gender, age, and overall health of the subject receiving the dosageof an anesthesia-reversing agent as disclosed herein, the route ofadministration, whether a composition comprising an anesthesia-reversingagent and/or salts thereof is administered in conjunction with othermolecules, or towards the end of the administration of the anesthesiaagent or after the stopping of the anesthesia agent, and the specificregimen of administration of the composition comprising ananesthesia-reversing agent and/or salts thereof. For example, ingeneral, intravenous or nasal administration requires a smaller dosagethan oral or enteral administration.

Other Formulations and Routes of Administration

In alternative embodiments, a composition comprising ananesthesia-reversing agent as disclosed herein is by an infusion pump(to infuse, for example, the compositions as disclosed herein into thesubject's circulatory system) is generally used intravenously, althoughsubcutaneous, arterial, and epidural infusions are occasionally used.Injectable forms of administration of an anesthesia-reversing agent asdisclosed herein are sometimes preferred for maximal effect.

Alternatively, in some embodiments, compositions as disclosed hereincomprising an anesthesia-reversing agent as disclosed herein and/orsalts thereof can also be administered to the nasal passages as a spray,as the nasal area provide a rapid and efficient access to the upperareas of the head. Sprays also provide immediate access to the pulmonarysystem and are the preferable methods for administering compositions tothese areas. Access to the gastrointestinal tract is gained using oral,enema, or injectable forms of administration. For example,administration of the compositions as disclosed herein comprising ananesthesia-reversing agent and/or salts thereof to a subject can beoral.

As indicated above, orally active compositions comprising ananesthesia-reversing agent as disclosed herein and/or salts thereof arepreferred for at least a portion of the cycle of therapy, as oraladministration is usually the safest, most convenient, and economicalmode of drug delivery. Consequently, compositions as disclosed hereincomprising an anesthesia-reversing agent as disclosed herein can bemodified to increase their oral bioavailability by reducing oreliminating their polarity. This can often be accomplished byformulating a composition with a complimentary reagent that neutralizesits polarity, or by modifying the compound with a neutralizing chemicalgroup. Oral bioavailability is also a problem, because drugs are exposedto the extremes of gastric pH and gastric enzymes. Accordingly, problemsassociated with oral bioavailability can be overcome by modifying themolecular structure to be able to withstand very low pH conditions andresist the enzymes of the gastric mucosa such as by neutralizing anionic group, by covalently bonding an ionic interaction, or bystabilizing or removing a disulfide bond or other relatively labilebond.

Compositions as disclosed herein comprising an anesthesia-reversingagent as disclosed herein and/or salts thereof can be physiologicallystable at therapeutically effective concentrations. Physiological stablecompounds of an anesthesia-reversing agent as disclosed herein or saltsthereof not break down or otherwise become ineffective uponadministration to a subject or prior to having a desired effect. Ananesthesia-reversing agent as disclosed herein can be structurallyresistant to catabolism, and, thus, physiologically stable, or coupledby electrostatic or covalent bonds to specific reagents to increasephysiological stability. Such reagents include amino acids such asarginine, glycine, alanine, asparagine, glutamine, histidine, or lysine,nucleic acids including nucleosides or nucleotides, or substituents suchas carbohydrates, saccharides and polysaccharides, lipids, fatty acids,proteins, or protein fragments. Useful coupling partners include, forexample, glycol, such as polyethylene glycol, glucose, glycerol,glycerin, and other related substances.

In some embodiments, compositions as disclosed herein comprising ananesthesia-reversing agent as disclosed herein and/or salts thereof areused in combination with other agents. For example, where thecompositions as disclosed herein comprising an anesthesia-reversingagent as disclosed herein and/or salts thereof are being used accordingto the methods as disclosed herein to reverse general anesthesia-inducedunconsciousness and aid recovery of mobility and cognitive function, acombination therapy can include administering a composition comprisingan anesthesia-reversing agent as disclosed herein and/or salts thereofand an additional agent, e.g., a pain medication, which are well knownin the art, and include for example, but are not limited to opioidanalgesics (e.g., morphine and the like) and/or regional anesthesia(i.e. epidurals, nerve blocks, etc). In some embodiments, a painmedication administered with an anesthesia-reversing agent as disclosedherein can include, for example, caffeine, for example ANACIN™,EXCEDRIN™ MIDOL™, VANQUISH™, FIORICET™, ESGIC PLUS™, CafergotSuppositories (other names: CAFERTRINE™, CAFETRATE™, MIGERGOT™,WIGRAINE™), Cafergot Tablets (other names: ERCAF™, ERGO-CAFF™,GOTAMINE™, WIGRAINE™), FIORINAL™ Capsules, FIORINAL™ with Codeine No. 3,NORGESIC FORTE™; NORPHADRINE FORTE™, NORGESIC™; TRIAMINICIN™ withCodeine Tablets and the like.

Physiological stability of a composition comprising ananesthesia-reversing agent as disclosed herein and/or salts thereof canbe measured from a number of parameters such as the half-life of theanesthesia-reversing agent or salts thereof, or the half-life of activemetabolic products derived from the anesthesia-reversing agent or saltsthereof. In some embodiments, compositions comprising ananesthesia-reversing agent as disclosed herein and/or salts thereof canhave in vivo half-lives of greater than about fifteen minutes, greaterthan about one hour, greater than about two hours, and greater thanabout four hours, eight hours, twelve hours, or longer. Ananesthesia-reversing agent as disclosed herein or its salts can bestable using this criteria, however, physiological stability can also bemeasured by observing the duration of biological effects on the patient.Clinical symptoms that are important from the patient's perspectiveinclude an increased rate of awakening from anesthesia-inducedunconsciousness as compared to passive awakening or emergence, orabsence of, or decreased occurrence or severity of delirium on awakeningas compared to passive awakening from general anesthesia-inducedunconsciousness. Preferably, a stable composition comprising ananesthesia-reversing agent and/or salts thereof has an in vivo half-lifeof greater than about 15 minutes, a serum half-life of greater thanabout 15 minutes, or a biological effect which continues for greaterthan 15 minutes after treatment has been terminated or the serum levelof the compound has decreased by more than half.

Preferably, compositions as disclosed herein comprising a ananesthesia-reversing agent and/or salts thereof are also notsignificantly biotransformed, degraded, or excreted by catabolicprocesses associated with metabolism. Although there may be somebiotransformation, degradation, or excretion, these functions are notsignificant, if the composition is able to exert its desired effect.

In some embodiments, compositions as disclosed herein comprising ananesthesia-reversing agent and/or salts thereof are also safe ateffective dosages. Safe compositions are compositions that are notsubstantially toxic (e.g. cytotoxic or myelotoxic), or mutagenic atrequired dosages, do not cause adverse reactions or side effects, andare well-tolerated. Although side effects may occur, compositions aresubstantially safe if the benefits achieved from their use outweighdisadvantages that may be attributable to side effects. Unwanted sideeffects include nausea, vomiting, hepatic or renal damage or failure,hypersensitivity, allergic reactions, cardiovascular problems,gastrointestinal disturbances, seizures, and other central nervoussystem difficulties, fever, bleeding or hemorrhaging, serumabnormalities, and respiratory difficulties.

Compositions useful for facilitating awakening or shortening theawakening period to full cognitive function and mobility after generalanesthesia-induced unconsciousness preferably do not substantiallyaffect the effectiveness of the surgery, post-surgery recovery period,or long term cognitive function of the subject.

Useful combination therapies will be understood and appreciated by thoseof skill in the art. Potential advantages of such combination therapiesinclude the ability to use less of each of the individual activeingredients to minimize toxic side effects, synergistic improvements inefficacy, improved ease of administration or use, and/or reduced overallexpense of compound preparation or formulation.

Administration of the composition comprising an anesthesia-reversingagent and/or salts thereof to a subject according to a method of theinvention may be for prophylaxis, e.g., to any subject awakening fromgeneral anesthesia-induced unconsciousness, or alternatively, fortherapeutic treatment of a subject identified with emergence delirium orfrom over sedation by the general anesthesia.

In some embodiments, the composition comprising an anesthesia-reversingagent and/or salts thereof can be used in prophylaxis treatment, forexample, where the subject who is at increased risk of delirium, e.g.,emergence delirium after general anesthesia, the subject can beadministered a composition comprising an anesthesia-reversing agentand/or salts thereof prior to, or concurrent with or subsequent to, thegeneral anesthesia agent, in order to prevent delirium on recoveringfrom unconsciousness.

In some embodiments, the composition comprising an anesthesia-reversingagent and/or salts thereof can be administered to an adult, anadolescent, a child, a neonate, an infant or in utero.

In some embodiments, the composition comprising an anesthesia-reversingagent and/or salts thereof can be administered according to a specificdosing regimen, e.g., in a single or multiple doses, or continuous orsporadic, or as deemed necessary based on an administration regime asdetermined by recovery of consciousness in the subject as disclosedherein in the Examples.

In some embodiments, a composition comprising an anesthesia-reversingagent and/or salts thereof can be administered to a subject via acontinuous infusion throughout the period the subject is recoveringconsciousness. Alternatively, a composition comprising ananesthesia-reversing agent and/or salts thereof can be administered tothe subject in multiple doses over a single span of a few minutes toseveral hours throughout the period the subject is recoveringconsciousness.

Alternatively, in some embodiments a composition comprising ananesthesia-reversing agent and/or salts thereof can be administered to asubject in a single parenteral bolus immediately after, or just beforestopping the administration of the general anesthesia agent.

In some embodiments, a composition comprising an anesthesia-reversingagent and/or salts thereof can be prepared in solution as a dispersion,mixture, liquid, spray, capsule, or as a dry solid such as a powder orpill, as appropriate or desired. Solid forms may be processed intotablets or capsules or mixed or dissolved with a liquid such as water,alcohol, saline or other salt solutions, glycerol, saccharides orpolysaccharide, oil, or a relatively inert solid or liquid. Liquids,pills, capsules or tablets administered orally may also includeflavoring agents to increase palatability. Additionally, in someembodiments, a composition comprising an anesthesia-reversing agentand/or salts thereof can further comprise agents to increase shelf-life,such as preservatives, anti-oxidants, and other components necessary andsuitable for manufacture and distribution of the composition.Compositions comprising an anesthesia-reversing agent and/or saltsthereof can further comprise a pharmaceutically acceptable carrier orexcipient. Carriers are chemical or multi-chemical compounds that do notsignificantly alter or affect the active ingredients of thecompositions. Examples include water, alcohols such as glycerol andpolyethylene glycol, glycerin, oils, salts such as sodium, potassium,magnesium, and ammonium, fatty acids, saccharides, or polysaccharides.Carriers may be single substances or chemical or physical combinationsof these substances.

In some embodiments, a composition comprising an anesthesia-reversingagent and/or salts thereof can contain chemicals that are substantiallynon-toxic. Substantially non-toxic means that the composition, althoughpossibly possessing some degree of toxicity, is not harmful to thelong-term health of the patient. Although the active component of thecomposition may not be toxic at the required levels, there may also beproblems associated with administering the necessary volume or amount ofthe final form of the composition to the patient. For example, ifcomposition comprising an anesthesia-reversing agent contains a salt,although the active ingredient may be at a concentration that is safeand effective, there can be a harmful build-up of sodium, potassium, oranother ion. With a reduced requirement for the composition or at leastthe active component of that composition, the likelihood of suchproblems can be reduced or even eliminated. Consequently, althoughpatients may suffer minor or short term detrimental side-effects, theadvantages of taking the composition outweigh the negative consequences.

In some embodiments, treatment of a subject with a compositioncomprising an anesthesia-reversing agent and/or salts thereof can beaccording to the methods as disclosed herein can be therapeutictreatment, e.g., a method of treatment of a emergence delirium or forrecovering a subject who is oversedated during general anesthesia. Insome embodiments, therapeutic treatment involves administration of acomposition comprising an anesthesia-reversing agent and/or saltsthereof according to the methods as disclosed herein to a patientsuffering from one or more symptoms of, or having been diagnosed asbeing afflicted with delirium postoperatively, or who is over-sedated byanesthesia during surgery. Therapeutic administration that providesrelief and even partial relief from one or more of a symptom of deliriummay correspond to an increased quality of surgical experience, and ofincreased quality of life if the over-sedation is life-threatening.Further, therapeutic treatment or preventative of a subject thatalleviate or prevent the occurrence a pathological symptom of deliriumcan allow for other treatments to be administered, e.g., post-operativewound dressing, pain medication as well as monitoring appropriatepost-operative responses.

In alternative embodiments, the treatment of a subject with acomposition comprising an anesthesia-reversing agent and/or saltsthereof can be according to the methods as disclosed herein can be aprophylactic treatment, for example, to decrease the time to fullcognitive function and consciousness after general anesthesia, and/or toprevent the occurrence of delirium in a subject post general-anesthesiaunconsciousness. In some embodiments, prophylactic treatments involveadministration of a composition comprising an anesthesia-reversing agentand/or salts thereof according to a method of the invention to a subjectundergoing general anesthesia, where it is desirable to have the subjectemerge from unconsciousness quicker than in the absence ofadministration of the anesthesia-reversing agent. Administration of acomposition comprising an anesthesia-reversing agent and/or saltsthereof can begin at the end or immediately after, or during (e.g.,concurrent with the decreasing dose of anesthesia agent) administrationof an anesthetic agent etc., and can continue, if necessary for a shortperiod of time, after the subject is conscious and gained mobility andcognitive function. As demonstrated herein, both prophylactic andtherapeutic uses are readily acceptable, because these compounds aregenerally safe and non-toxic.

Doses of Administration

The amount of an anesthesia-reversing agent that can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound that produces a therapeutic effect. Generally outof one hundred percent, this amount will range from about 0.01% to 99%of the compound, preferably from about 5% to about 70%, most preferablyfrom 10% to about 30%.

The data obtained from the animal model experiments as disclosed hereinin the Examples can be used in formulating a range of dosage for use inhumans. The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED50 (the dosetherapeutically effective in 50% of the population) with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized.

The therapeutically effective dose of an anesthesia-reversing agent canbe estimated initially from animal studies, for example, one can measurethe % recovery from consciousness in rats, the rate of recovery toconsciousness, respiratory rate and tidal volume, and righting within 30minutes of administration of an anesthesia-reversing agent, as disclosedherein in the Examples. A dose may be formulated in animal models toachieve a circulating plasma concentration range that includes the IC₅₀(i.e., the concentration of the therapeutic which achieves ahalf-maximal inhibition of symptoms) as determined in animal models.Levels of an anesthesia-reversing agent in the plasma of an animal modelmay be measured, for example, by high performance liquid chromatography.The effects of any particular dosage can be monitored by a suitablebioassay.

The dosage of an anesthesia-reversing agent may be determined by aphysician and adjusted, as necessary, to suit observed effects of thetreatment. Generally, the compositions are administered so that ananesthesia-reversing agent or a prodrug thereof is given at a dose fromany of: 1 μg/kg to 150 mg/kg, 1 μg/kg to 100 mg/kg, 1 μg/kg to 50 mg/kg,1 μg/kg to 20 mg/kg, 1 μg/kg to 10 mg/kg, 1 μg/kg to 50 mg/kg, 100 μg/kgto 100 mg/kg, 100 μg/kg to 50 mg/kg, 100 μg/kg to 20 mg/kg, 100 μg/kg to10 mg/kg, 100 μg/kg to 1 mg/kg, 1 mg/kg to 100 mg/kg, 1 mg/kg to 50mg/kg, 1 mg/kg to 20 mg/kg, 1 mg/kg to 10 mg/kg, 10 mg/kg to 100 mg/kg,10 mg/kg to 50 mg/kg, or 10 mg/kg to 20 mg/kg. It is to be understoodthat ranges given here include all intermediate ranges, for example, therange 0.1 mg/kg to 10 mg/kg includes about 0.1 mg/kg to 1 mg/kg, 1 mg/kgto 2 mg/kg, 1 mg/kg to 3 mg/kg, 1 mg/kg to 4 mg/kg, 1 mg/kg to 5 mg/kg,1 mg/kg to 6 mg/kg, 1 mg/kg to 7 mg/kg, 1 mg/kg to 8 mg/kg, 1 mg/kg to 9mg/kg, 2 mg/kg to 10 mg/kg, 3 mg/kg to 10 mg/kg, 4 mg/kg to 10 mg/kg, 5mg/kg to 10 mg/kg, 6 mg/kg to 10 mg/kg, 7 mg/kg to 10 mg/kg, 8 mg/kg to10 mg/kg, 9 mg/kg to 10 mg/kg, and the like. It is to be furtherunderstood that the ranges intermediate to the given above are alsowithin the scope of this invention, for example, in the range 1 mg/kg to10 mg/kg, dose ranges such as 2 mg/kg to 8 mg/kg, 3 mg/kg to 7 mg/kg, 4mg/kg to 6 mg/kg, and the like. In some embodiments, the dose is 0.1mg/kg to 5 mg/kg, or between about 5 mg/kg to 10 mg/kg.

In some embodiments, the compositions comprising an anesthesia-reversingagent are administered at a dosage so that an anesthesia-reversing agentor a metabolite thereof has an in vivo, e.g., serum or blood,concentration of less than 500 nM, less than 400 nM, less than 300 nM,less than 250 nM, less than 200 nM, less than 150 nM, less than 100 nM,less than 50 nM, less than 25 nM, less than 20, nM, less than 10 nM,less than 5 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, lessthan 0.05, less than 0.01, nM, less than 0.005 nM, or less than 0.001 nMafter 15 mins, 30 mins, 1 hr, 1.5 hrs, 2 hrs, 2.5 hrs, 3 hrs, 4 hrs, 5hrs, 6 hrs, 7 hrs, 8 hrs, 9 hrs, 10 hrs, 11 hrs, 12 hrs or more of timeafter the time of administration.

With respect to duration and frequency of treatment, it is typical forskilled clinicians to monitor subjects in order to determine when thetreatment is providing therapeutic benefit, and to determine whether toincrease or decrease dosage, increase or decrease administrationfrequency, discontinue treatment, resume treatment or make otheralteration to treatment regimen. The dosing schedule can vary from onceevery 10 to 30 minutes depending on a number of clinical factors, suchas the subject's sensitivity to an anesthesia-reversing agent. Thedesired dose can be administered at one time or divided into subdoses,e.g., 2-4 subdoses and administered over a period of time, e.g., atappropriate intervals through the subject awakening to consciousness orother appropriate schedule. Such sub-doses can be administered as unitdosage forms.

An anesthesia-reversing agent or a prodrug thereof can be administratedto a subject in combination with one or more pharmaceutically activeagents. Exemplary pharmaceutically active compound include, but are notlimited to, those found in Harrison's Principles of Internal Medicine,13^(th) Edition, Eds. T. R. Harrison et al. McGraw-Hill N.Y., NY;Physicians Desk Reference, 50^(th) Edition, 1997, Oradell N.J., MedicalEconomics Co.; Pharmacological Basis of Therapeutics, 8th Edition,Goodman and Gilman, 1990; United States Pharmacopeia, The NationalFormulary, USP XII NF XVII, 1990; current edition of Goodman andOilman's The Pharmacological Basis of Therapeutics; and current editionof The Merck Index, the complete content of all of which are hereinincorporated in its entirety.

Articles of Manufacture

The invention includes articles of manufacture, which comprise ananesthesia-reversing agent as disclosed herein, e.g., any one or acombination of methylphenidate (MPH), amphetamine, modafinil,amantadine, caffeine, or a prodrug or analogue thereof and labelingstating that the anesthesia-reversing agent is effective for reversinggeneral anesthesia-induced unconsciousness and aiding recovery ofcognitive function after general anesthesia. The anesthesia-reversingagent present in this article of manufacture may be methylphenidate(MPH), amphetamine, modafinil, amantadine, caffeine, or a prodrug oranalogue thereof. The article of manufacture can comprise themethylphenidate (MPH), amphetamine, modafinil, amantadine, caffeine, ora prodrug or analogue thereof as the only active agent or may includeone or more additional active agents or therapeutic agents, e.g.,analgesics or pain-reducing agents. Additional active agents may becombined in a single dosage form with the anesthesia-reducing agent,e.g., methylphenidate (MPH), amphetamine, modafinil, amantadine,caffeine, or a prodrug or analogue thereof or may be packaged asseparate dosage forms. The article of manufacture may comprise packagingmaterial and a dosage form of anesthesia-reducing agent, e.g.,methylphenidate (MPH), amphetamine, modafinil, amantadine, caffeinecontained within the packaging material, wherein the packaging materialcomprises a label approved by a regulatory agency for the product. Incertain embodiments the labeling is labeling approved by the UnitedStates FDA.

An example of an article of manufacture provided by the invention is apackaged pharmaceutical compositions comprising an anesthesia-reducingagent, e.g., any one or a combination of methylphenidate (MPH),amphetamine, modafinil, amantadine, caffeine in a container and printedlabeling stating that the anesthesia-reducing agent, e.g.,methylphenidate (MPH), amphetamine, modafinil, amantadine, caffeine isuseful for reversing general anesthesia-induced unconsciousness andaiding recovery of cognitive function after general anesthesia.

When an article of manufacture of this invention comprisesmethylphenidate (MPH), the labeling may advise administering a rangebetween 10 mg/kg to 5 mg/kg, or 5 mg/kg to 0.1 mg/kg per dose to awakena subject from anesthesia-induced unconsciousness. The labeling can alsoadvise that methylphenidate (MPH) is to be administered via intravenousadministration, but there can be alternative routes by whichmethylphenidate (MPH) can be administered.

Various embodiments of the disclosure could also include permutations ofthe various elements recited in the claims as if each dependent claimwas a multiple dependent claim incorporating the limitations of each ofthe preceding dependent claims as well as the independent claims. Suchpermutations are expressly within the scope of this disclosure.

While the invention has been particularly shown and described withreference to a number of embodiments, it would be understood by thoseskilled in the art that changes in the form and details may be made tothe various embodiments disclosed herein without departing from thespirit and scope of the invention and that the various embodimentsdisclosed herein are not intended to act as limitations on the scope ofthe claims. All references cited herein are incorporated in theirentirety by reference

EXAMPLES

Materials and Methods.

Animal Care and Use. Animal studies were approved by the Subcommittee onResearch Animal Care, Massachusetts General Hospital, Boston, Mass. MaleSprague-Dawley rats (Charles River Laboratories, Wilmington, Mass.)weighing 351-565 grams were used. For the experiments to determine timeto emergence, as well as the methylphenidate dose-response studies undercontinuous isoflurane general anesthesia, experiments were performedusing the same 12 rats in random order. Separate groups of animals wereused for the electroencephalogram (4 rats), plethysmography (4 rats),and blood gas studies (6 rats). In animals that underwent multipleexperiments, each animal was provided with at least 3 days of restbetween experiments. Animals were kept on a standard day-night cycle(lights on at 7 AM, and off at 7 PM), and all experiments were performedduring the day.

Anesthetizing Protocol. Rats were anesthetized in an induction chamberwith 2-3% isoflurane in oxygen prior to placement of a lateral tail veinintravenous catheter (24 gauge, 19 mm). A rectal temperature probe wasinserted and the animal was placed in a cylindrical acrylicanesthetizing chamber. The chamber was custom-built and equipped withports for anesthetic gas delivery, sampling, and scavenging, as well asintravenous drug administration. A heating pad was placed under thechamber to keep the animal warm, and the body temperature was keptbetween 36.5° C. and 37.4° C.

The volume of the chamber was 4.6 liters. Initially the chamber wasprimed with isoflurane at a fresh gas flow rate of 2-3 liters/min, andthen the rate was lowered to 1-2 liters/min. The carrier gas was oxygen.Gas was continuously sampled from the distal portion of the chamber(opposite from the fresh gas inlet) and isoflurane, oxygen, and carbondioxide concentrations in the chamber were monitored using a calibratedOhmeda 5250 anesthetic agent analyzer (GE Healthcare, Waukesha, Wis.).

Preparation and Delivery of Drugs. Isoflurane, methylphenidatehydrochloride, and droperidol were purchased from Henry Schein(Melville, N.Y.), Sigma-Aldrich (St. Louis, Mo.), and American Regent(Shirley, N.Y.), respectively. Normal saline, methylphenidate, anddroperidol were always administered intravenously. Methylphenidate wasweighed, dissolved in 0.5 ml of normal saline, and sterile filteredimmediately prior to administration. Droperidol was diluted in normalsaline to a final volume of 0.5 ml prior to administration. Theintravenous tubing (approximate volume 0.6 ml) was always flushed with 2ml of normal saline after methylphenidate or droperidol to ensurecomplete delivery of drug.

Time to Emergence after a Standardized Isoflurane General Anesthetic. Totest the hypothesis that methylphenidate decreases time to emergencefrom a standardized isoflurane anesthetic, an endpoint that has beenused in several recent studies of anesthetic emergence,^(5,6,10) theinhaled concentration of isoflurane was fixed at 1.5% (˜1 MAC). After 40minutes, rats received either normal saline or methylphenidate (5 mg/kgIV). Isoflurane was continued for five additional minutes, then the ratwas taken out of the chamber and the temperature probe was removed. Theanimal was placed supine on a warming pad and inspired room air. Time toemergence was defined as the time from termination of isoflurane toreturn of righting (i.e. all four paws touching the floor).

Administration of Methylphenidate During Continuous Isoflurane GeneralAnesthesia. The rat was positioned supine in the anesthetizing chamberand the inhaled concentration of isoflurane was initially fixed at 2.0%for 20 minutes, then reduced to 0.8% over 15-20 minutes, and thenmaintained at 0.8% for 40 minutes. If the rat made any purposefulmovement, the isoflurane concentration was increased by 0.1% andmaintained for another 40 minutes. This process was repeated until thefinal dose of isoflurane sufficient to maintain loss of righting reflexwas established, and this dose was administered throughout the remainderof the experiment. This protocol was based on previously publishedmethods described by Alkire et al.^(4,11) After the final 40-minuteequilibration period, normal saline (2 ml) was administered and therectal temperature probe was removed. Five minutes later,methylphenidate was administered. To establish a dose-responserelationship, the inventors administered three different doses ofmethylphenidate (0.05 mg/kg, 0.5 mg/kg, or 5 mg/kg IV) on differentdays. After administration of methylphenidate, each animal continued toinhale the same dose of isoflurane for 30 minutes, or until restorationof righting occurred.

Electroencephalogram electrode placement, recording, and spectralanalysis. Extradural electroencephalogram electrodes were surgicallyimplanted at least 7 days prior to recording. General anesthesia wasinduced with xylazine (5-10 mg/kg IP) and ketamine (50-100 mg/kg IP),and supplemented with isoflurane (1-2%). A microdrill was used to makefour holes at the following stereotactic coordinates: A0L0, A6L3, A6L-3,and A10L2 relative to the lambda.¹² Polytetrafluoroethylene coated, 200μm diameter stainless steel electrode wires (A-M Systems, Sequim, Wash.)were inserted and secured with small stainless steel screws, andpermanently fixed with dental acrylic cement. Carprofen (5 mg/kg SC) wasadministered for analgesia on the day of surgery, as well as onpost-operative days 1, and 2. The potential difference betweenelectrodes A0L0 and A6L3, or between electrodes A0L0 and A6L-3(whichever gave less motion artifact), was referenced to A10L2 andrecorded using a QP511 Quad AC Amplifier System (Grass Instruments, WestWarwick, R.I.) and a USB-6009 14-bit data acquisition board (NationalInstruments, Austin, Tex.). Data was filtered between 0.3-100 Hz. Noline filter was used. The sampling rate was 512 Hz. After baselinerecordings were taken for 10 minutes while awake, rats were anesthetizedwith isoflurane and placed in the anesthetizing chamber. Although theinventors initially attempted to perform the electroencephalogramexperiments simultaneously with the behavioral experiments describedabove, the inventors found that the righting attempts produced too manymotion artifacts. Therefore the inventors performed theelectroencephalogram experiments in the prone position with theisoflurane dose fixed at 1.0%. These modifications allowed us tominimize electroencephalogram motion artifacts without restraining theanimals. After a minimum isoflurane exposure of 40 minutes, normalsaline was administered and the temperature probe was removed. Fiveminutes later, methylphenidate was administered. Spectral analysis wasperformed using Matlab 7.11 (Mathworks, Natick, Mass.) and the Chronuxsoftware (Cold Spring Harbor, N.Y.). 13 Spectrograms were calculatedusing sliding windows of 2 sec duration stepped through 0.05 sec. Foreach window, multitaper spectrum estimation was performed using 5tapers. The resulting spectral estimates have a bandwidth of ±1.5 Hz.Mean power spectra were compared before and after methylphenidateadministration using Kolmogorov-Smirnov tests.14 To determine thedifference between two spectra, a two sample Kolmogorov-Smirnov test 15was performed on the spectral power as a function of frequency computedfrom the 30 windows in the pre-methylphenidate and post-methylphenidateperiods. The inventors used a Bonferroni correction to adjust thesignificance level for multiple hypothesis testing.

Plethysmography. Rats were placed in a custom built plethysmographychamber and the isoflurane concentration in the chamber was maintainedat 1.5%. After equilibration in the chamber for 30 minutes, normalsaline or droperidol (0.5 mg/kg IV) was administered five minutes priorto methylphenidate (5 mg/kg IV). Because plethysmography recordings arevery sensitive to motion artifacts, the inventors used a higherisoflurane dose (1.5% or ^(˜)1 MAC), since animals at this dose ofisoflurane did not exhibit purposeful movements after methylphenidatewas administered. A differential pressure transducer and demodulator(Models CD15 and MP45-14-871; Validyne Engineering, Northridge, Calif.)were used to convert the chamber pressure to an analog signal. Thesignal was high pass filtered at 15 sec, acquired at 100 Hz, andanalyzed in four second epochs using a USB-6009 data acquisition board(National Instruments, Austin, Tex.) and LabView Software (version 8.5for Macintosh). Chamber carbon dioxide levels were maintained at or lessthan 0.5% in the open flow configuration. A heating pad was used to warmthe rat from beneath. Chamber air temperature and relative humidity weremeasured with a thermometer-hygrometer (Fisher Scientific, Pittsburgh,Pa.) and used to estimate tidal volumes during intermittent chamberclosure using methods described by Drorbaugh et al.¹⁶

Arterial Blood Gas and Hemodynamic Recordings. Rats with femoral arterycatheters (Charles River Laboratories, Wilmington, Mass.) were placed inthe anesthetizing chamber after lateral tail vein IV catheter placement.The isoflurane dose was kept constant at 1.5%. Mean arterial bloodpressure and heart rate were measured using a pressure transducer(TruWave, Edwards Life Sciences, Irvine, Calif.) interfaced with acustom-built amplifier (AD620 operational amplifier, Jameco Electronics,Belmont, Calif.). The signal was digitized at 1,000 Hz using a USB-6009data acquisition board (National Instruments, Austin, Tex.) and analyzedin four-second epochs. A pre-methylphenidate arterial blood sample wasdrawn following at least 30 minutes of equilibration in 1.5% isoflurane,and a postmethylphenidate sample was drawn 15 minutes aftermethylphenidate administration. Samples were promptly analyzed usingCG4+ cartridges in a Vetscan iStat 1 (Abaxis, Union City, Calif.) bloodgas analyzer.

Statistical analysis of the effect of methylphenidate on emergencetimes, return of righting responses and spectrograms. Prism 4.03(Graphpad Software, San Diego, Calif.) and Matlab (Mathworks, Natick,Mass.) were used for statistical analysis and where possible, resultsare reported in terms of 95% confidence intervals based on z-tests,t-tests or Mann-Whitney tests. The inventors used a Bayesian Monte Carloprocedure to compute Bayesian 95% (credibility) confidence intervals toassess the effect of methylphenidate dose on return of righting duringcontinuous isoflurane general anesthesia¹⁷. For this computation theinventors assumed a binomial model as the sampling density or likelihoodfunction for the propensity of animals in a given group to have returnof the righting response. The inventors took as the prior density foreach group the uniform density on the interval (0, 1) because it isuninformative. Because of the conjugacy between the prior and thelikelihood the posterior density for each group is a beta density.¹⁷ Theposterior densities for the differences in the proportion of animalsthat had return of righting were then computed by using standard Matlabsimulation procedures. Instead of p-values for the Bayesian analyses theinventors computed the posterior probability that the propensity toright was greater in on group compared to the other.

A one-way ANOVA was used to assess whether there were significantdifferences among the final isoflurane doses of animals that receivedthe 3 different doses of methylphenidate. To provide a conservativecheck on the assessments made by the 95% confidence intervals and theparametric tests and non-parametric tests were also used to assessstatistical significance. The Mann-Whitney test was used to test thehypothesis that methylphenidate hastens time to emergence fromisoflurane general anesthesia, and to test the dose-dependence ofmethylphenidate on time to righting during continuous isoflurane generalanesthesia. A paired t-test was used to test the hypothesis thatmethylphenidate produces a respiratory alkalosis during isofluranegeneral anesthesia. The inventors used the two-sided Kolmogorov-Smirnovtest with a Bonferonni correction to compare spectra in animals beforeand after receiving methylphenidate. The inventors considered a resultto be statistically significant based on the 95% confidence intervalscomparing two groups if zero was not in the interval, based onhypothesis tests if the p-values were less than 0.05 or in the case ofthe Bayesian analyses, if the relevant posterior probability was greaterthan 0.95.

Statistical analysis of the effect of methylphenidate on respiratoryrate, mean arterial blood pressure, and heart rate. To estimate theeffect of methylphenidate on respiratory and cardiovascular variables,the inventors performed within-animal analyses because the inventors hadsufficient samples to estimate the mean of each variable and itsstandard error before and after drug administration for each animal. Todo so, the inventors performed time-series modeling of thesemeasurements to take account of their serial dependence and thereby,compute appropriate estimates of variance for within-animal two samplez-tests. That is, the inventors fit different autoregressive models oforder p (AR(p)) with a nonzero mean to the data before and after theadministration of methylphenidate. Because these models have a non-zeromean, the inventors devised an efficient cyclic descent parameterestimation algorithm.¹⁸ Within the cyclic descent algorithm theinventors used the least-squares algorithm to estimate the AR parametersand conditional maximum likelihood estimation to compute the mean andvariance paranneters.¹⁴ The cyclic descent algorithm iterated betweenthe least-squares and the conditional maximum likelihood proceduresuntil convergence was achieved. The inventors allowed the order of theAR (p) model to be different for each segment. The inventors chose thebest order p of the AR model on each segment using Akaike's InformationCriterion.¹⁴ The inventors computed the approximate standard errors ofthe parameters by estimating the parameter covariance matrix as theinverse of the observed Fisher information matrix.¹⁹ By design, thesestandard errors of the parameters take account of the serial dependencein the data. The estimated mean and standard error of the mean were usedto compute the 95% confidence interval for the difference between thephysiological variable before and after methylphenidate based on az-statistic.

Example 1

The inventors herein assessed if methylphenidate (MPH) induces emergencefrom isoflurane anesthesia. The inventors first tested whethermethylphenidate affects time to emergence from a standardized generalanesthetic with isoflurane. The inventors then assessed two possiblemechanisms by which methylphenidate may act: (1) increased arousal, or(2) increased minute ventilation. To test for increased arousal, theinventors performed experiments to assess whether methylphenidateinduces restoration of righting under continuous isoflurane anesthesia.The inventors also performed spectral analysis of electroencephalogramrecordings to assess changes induced by methylphenidate duringcontinuous isoflurane anesthesia. To test for increased minuteventilation, the inventors obtained plethysmography and arterial bloodgas data to analyze changes in respiratory status induced bymethylphenidate.

Thus, one aspect of the present invention is based on the inventorsdiscovery that in a rat animal model, intravenous dextro-methylphenidate(d-MPH), levo-MPH, and racemic MPH rapidly reversed isoflurane-inducedgeneral anesthesia. The inventors next assessed if other drugs may beclinically useful to actively reverse general anesthesia. One aspect ofthe present invention is directed to use of dextro-amphetamine,amphetamine, modafinil, amantadine, caffeine, or a product containingany of these drugs, to reverse the state of general anesthesia when itis no longer desired (e.g. at the end of surgery).

Accordingly, herein the inventors demonstrate that anesthesia-reversingagents dextro-amphetamine, amphetamine, modafinil, amantadine, caffeine,or a product containing any of these drugs, prepared as a sterilesolution for intravenous injection can be used for reversing effects ofgeneral anesthesia. The inventors compositions comprisinganesthesia-reversing agents have a widespread usefulness in patients torapidly reverse the state of general anesthesia when it is no longerdesired (e.g. at the end of surgery). In addition, anesthesia-reversingagents are useful as a “rescue” drug in patients who are accidentallyoversedated and become unresponsive or apneic during conscious sedation.Finally, the anesthesia-reversing agents as disclosed herein also haveutility for the treatment of emergence delirium, a serious clinicalproblem with an incidence as high as 30% in pediatric patientsundergoing general anesthesia.

Using adult rats, the inventors assessed the effect of methylphenidateIV on time to emergence from isoflurane anesthesia. The inventors thenperformed experiments to test separately for methylphenidate-inducedchanges in arousal and changes in minute ventilation. A dose responsestudy was performed to test for methylphenidate-induced restoration ofrighting during continuous isoflurane anesthesia. Surfaceelectroencephalogram recordings were performed to observeneurophysiological changes. Plethysmography recordings and arterialblood gas analysis were performed to assess methylphenidate-inducedchanges in respiratory function. Droperidol IV was administered to testfor inhibition of methylphenidate's actions.

Example 2

Methylphenidate hastens time to emergence from a standardized isofluraneanesthetic. FIG. 1A provides a schematic of the protocol for thisexperiment. As shown in FIG. 1B, the median time to emergence foranimals that received normal saline was 280 seconds (n=12), versus 91seconds (n=12) for animals that received methylphenidate (5 mg/kg IV).The median difference in time to emergence between these two groups was200 seconds with a 95% confidence interval computed using theMann-Whitney test of [155, 331] seconds. This median difference wasstatistically significant (p<0.0001, two-sided Mann-Whitney test). The %recovery of consciousness in rats of was faster for D-MGH than L-MPH, asshown in FIG. 7 .

Methylphenidate Induces Emergence During Continuous Inhalation ofIsoflurane

To assess if methylphenidate increases arousal, the inventors performedthe following experiments during continuous inhalation of isoflurane.Because isoflurane was not discontinued, any emergence mechanisminvolving accelerated isoflurane excretion would not be possible. At thestart of these experiments (FIG. 2A) the minimum concentration ofinhaled isoflurane sufficient to maintain loss of righting wasestablished for each rat (see Materials and Methods for details), andthis dose was continuously delivered to the chamber throughout theexperiment. The final dose of isoflurane was 0.9%±0.1% (mean±SD). Afterequilibration, none of the animals exhibited purposeful movement inresponse to intravenous injection of normal saline or removal of thetemperature probe, indicating that mild stimulation did not producearousal at this depth of anesthesia. Five minutes after normal saline,methylphenidate was administered. At the maximum dose of 5 mg/kg,purposeful movements (e.g. lifting of the head, opening of the eyes,twisting of the torso, kicking, clawing, chewing, licking, and grooming)were observed within 30 seconds for all 12 rats, despite continuousinhalation of isoflurane at the same, fixed dose. All of the ratsremained very active and continued to move about in the chamber afterrighting. Per the animal protocol, the inventors concluded theexperiment after the righting reflex was restored. As shown in FIG. 2B,return of righting occurred in 11 of 12 rats after administration ofmethylphenidate at this dose. Return of righting also occurred in 11 of12 rats after administration of a 10-fold lower dose (0.5 mg/kg IV), butthere were no signs of arousal in any of the six rats that received 0.05mg/kg. The Bayesian 95% confidence interval for the difference in thepropensities to have return of righting between rats in the 5 mg/kgmethylphenidate group and those in the 0.05 mg/kg methylphenidate groupwas [0.39, 0.94]. The Bayesian 95% confidence interval for thedifference in the propensities to have return of righting between ratsin the 0.5 mg/kg methylphenidate group and those in the 0.05 mg/kgmethylphenidate group was [0.40, 0.94]. For both comparisons theposterior probability was 0.999 indicating that the two differences arehighly significant. As shown in FIG. 2C, the median time to rightingafter methylphenidate during continuous inhalation of isoflurane was 181seconds for rats that received 5 mg/kg, and 348 seconds for rats thatreceived 0.5 mg/kg. The median difference in time to righting duringcontinuous inhalation of isoflurane between these two groups was 173seconds with a 95% confidence interval computed using the Mann-Whitneytest of [50, 332] seconds. This median difference was statisticallysignificant (p=0.01, two-sided Mann-Whitney test). There was nostatistically significant difference in the final isoflurane dose amongthe animals that received the 3 different doses of methylphenidate(p=0.3, F-test for one-way ANOVA).

Example 3

Droperidol Inhibits Methylphenidate-Induced Emergence Behavior

In a group of animals (n=6) continuously inhaling isoflurane at a dosesufficient to maintain loss of righting as above, the protocolillustrated in FIG. 2A was repeated with the exception that droperidol(0.5 mg/kg IV) was administered in place of normal saline. None of theanimals exhibited purposeful movement in response to the administrationof droperidol or subsequent removal of the temperature probe. Fiveminutes after droperidol, the highest dose of methylphenidate used inthis study (5 mg/kg) was administered. These animals generally exhibitedno purposeful movement after methylphenidate administration, althoughsome sluggish limb movements were occasionally observed. None of theseanimals had return of righting, compared to the 11 of 12 animals thathad return of righting after receiving normal saline prior to the samedose of methylphenidate (FIG. 2D). The 95% Bayesian confidence intervalfor the difference in righting propensity between these two conditionsis [0.39, 0.94]. The posterior probability that the propensity to rightfor those that received saline was greater than that for those thatreceived droperidol was 0.999, indicating a highly significantdifference.

Droperidol Inhibits Methylphenidate-Induced Electroencephalogram ChangesDuring Continuous Inhalation of Isoflurane.

Electroencephalogram data was recorded from rats with pre-implantedextradural skull electrodes (n=4). Results from an individual rat areshown in FIG. 3A. In the awake state before the administration of anydrugs, animals showed an active high-frequency, low-amplitudeelectroencephalogram pattern, which changed to a low-frequency,high-amplitude pattern during continuous inhalation of isoflurane(1.0%). Although the electroencephalogram pattern did not change afterinjection of normal saline or removal of the temperature probe,administration of methylphenidate (5 mg/kg IV) induced a prompt shiftwithin 30 seconds back to an active high frequency, low-amplitudepattern similar to that observed during the awake state. This changepersisted for more than 15 minutes. FIG. 3B shows 30-second epochs ofraw electroencephalogram recordings from a single animal that receiveddroperidol (0.5 mg/kg IV) five minutes prior to methylphenidate (5 mg/kgIV). After droperidol administration, methylphenidate did not induceelectroencephalogram changes consistent with arousal.

To assess changes in electroencephalogram power over time, spectrogramswere computed from the continuous electroencephalogram data recordedfrom each animal. Typical results from individual rats are shown in FIG.4 . During the awake state (FIG. 4A), electroencephalogram power wasmainly in the theta frequency range (4-8 Hz). However, continuousinhalation of 1.0% isoflurane (FIG. 4B) caused a large increase in deltapower (<4 Hz). Although intravenous injection of normal saline producedno appreciable change in the power spectrum, administration ofmethylphenidate (5 mg/kg IV) produced a prompt shift in power from deltato theta. When droperidol (0.5 mg/kg IV) was administered instead ofnormal saline, however, methylphenidate failed to induce theseelectroencephalogram changes (FIG. 4C).

FIG. 5 shows spectrograms and power spectra with the results of theKolmogorov-Smirnov test computed from two-minute time windows before andafter methylphenidate administration. At a 0.05 significance level thetwo-sided Kolmogorov-Smirnov test with Bonferonni correction rejects thenull hypothesis at all frequencies except those marked with whitesquares. In four rats that received normal saline (FIG. 5A),methylphenidate (5 mg/kg IV) induced a rapid shift in peak power fromdelta to theta, and the difference in power before and aftermethylphenidate was statistically significant at most frequenciesbetween 0-10 Hz (twosided Kolmogorov-Smirnov test, p<0.05). However, asshown in FIG. 5B, four rats that received droperidol (0.5 mg/kg IV)prior to methylphenidate only had small, statistically significantdecreases in delta power (two-sided Kolmogorov-Smirnov test, p<0.05),and the shift in peak power from delta to theta was absent.

Example 4

Methylphenidate Induces an Increase in Minute Ventilation that isInhibited by Droperidol.

As demonstrated in the representative result shown in FIG. 6A,methylphenidate (5 mg/kg) induced a substantial increase in respiratoryrate during continuous inhalation of isoflurane (1.5%). At this dose ofisoflurane, purposeful movements consistent with arousal were notinduced by methylphenidate. Within-animal analysis demonstrated thatmethylphenidate induced a statistically significant increase inrespiratory rate for each animal that ranged from 10 to 51 breaths perminute (Table 1, two-sided z-test within-animal corrected for serialcorrelation, all p<10-16). Although two of the four rats hadstatistically significant changes in tidal volume, the changes weresmall and inconsistent. As demonstrated in the typical result shown inFIG. 6B, when droperidol (0.5 mg/kg IV) was administered instead ofnormal saline five minutes prior to methylphenidate (5 mg/kg IV), therewas only a negligible increase in respiratory rate. Within-animalanalysis revealed that methylphenidate produced a statisticallysignificant increase in respiratory rate in each of these animals thatranged from 2 to 5 breaths per minute (Table 2, two-sided z-testwithin-animal corrected for serial correlation, all p<0.0001). However,those increases were appreciably smaller than the 10 to 51 breaths perminute increases observed in the animals that were pretreated withnormal saline. Although all four rats had statistically significantchanges in tidal volume, the changes were small (4-17%) and inconsistent(one had an increase, while the other three had decreases).

TABLE 1 Respiratory rate (RR, breaths per minute) in individual animalspretreated with normal saline during isoflurane general anesthesia. Cl =confidence interval, RR = respiratory rate. Animal 1 2 3 4 RR beforemethylphenidate 83.4 84.3 103.5 97.8 (mean, [95% Cl]) [81.5, 85.4][83.5, 85.2] [98.4, 108.5] [96.3, 99.3] RR after 5 mg/kg IV 112.6 94.2153.8 116.7 Methylphenidate (mean, [95% Cl]) [109.5, 115.7] [93.4, 95.0][150.5, 157.2] [114.0, 119.4] Change in mean RR (mean, 95% Cl]) +29.2+9.8 +50.36 +18.9 [+25.5, +32.9] [+8.7, +11.0] [+44.3, +56.4] [+15.8,+21.9] z-statistic 15.9 16.6 16.7 12.3 p-value <10⁻¹⁶ <10⁻¹⁶ <10⁻¹⁶<10⁻¹⁵

TABLE 2 Respiratory Rate (RR, breaths per minute) in individual animalspretreated with droperidol (0.5 mg/kg IV) during isoflurane generalanesthesia. Cl = confidence interval, RR =respiratory rate. Animal 1 2 34 RR before methylphenidate 81.9 75.8 80.5 70.6 (mean, [95% Cl]) [80.7,83.0] [75.2, 76.4] [79.8, 81.2] [69.2, 72.0] RR after 5 mg/kg IV 86.378.0 84.1 75.5 Methylphenidate (mean, [95% Cl]) [85.8, 86.8] [77.1,78.9] [83.4, 84.9] [74.9, 76.1] Change in mean RR (mean, 95% Cl]) +4.4+2.2 +3.6 +4.9 [3.2, +5.7] [+1.1, +3.3] [+2.6, +4.6] [+3.3, +6.4]z-statistic 7.0 4.1 7.0 6.3 p-value <0.0001 <0.0001 <0.0001 <0.0001

Methylphenidate Induces a Significant Respiratory Alkalosis and SmallHemodynamic Changes During Isoflurane General Anesthesia.

As shown in Table 3, during continuous isoflurane anesthesia there werestatistically significant changes in arterial pH and paCO2 after theadministration of methylphenidate. Assuming no change in baselinemetabolism, the calculated increase in alveolar ventilation (VA) was24±6% using the relationship VApost/VApre=(paCO2)pre/(paCO2)post, where“pre” and “post” denote pre-methylphenidate and post-methylphenidate,respectively. The slight increase in PaO2 after methylphenidate was notstatistically significant (two-sided paired t test, p=0.14).Within-animal analyses showed that 4 animals had statisticallysignificant increases in mean arterial blood pressure (3 to 20 mmHg)while 2 had no significant change (Table 4). Four animals hadinsignificant increases in heart rate and 2 had small, but statisticallysignificant increases (6 and 15 beats per minute) in heart rate (Table5).

TABLE 3 Arterial blood gas analysis during isoflurane general anesthesia(n = 6). Cl = confidence interval, RR = respiratory rate. P₂CO₂ P₂O₂ pH(mmHg) (mmHg) before methylphenidate 7.45 43 226 (mean, [95% Cl]) [7.41,7.50] [40, 47] [200, 252] after 5 mg/kg IV 7.51 35 241 Methylphenidate[7.46, 7.55] [32, 38] [211, 270] (mean, [95% Cl]) p-value (paired ttest) 0.004 0.0001 0.144

TABLE 4 Mean arterial blood pressure (MAP, mmHg) in individual animalsduring isoflurane general anesthesia. CI = confidence interval, RR =respiratory rate. Animal 1 2 3 4 5 6 MAP before 96.6 82.6 88.1 86.7100.2 83.4 methylphenidate (mean, [96.3, 96.9] [81.7, 83.5] [87.7, 88.4][86.1, 87.2] [99.7, 100.8] [82.7, 84.1] [95% CI) MAP after 5 mg/kg IV117.1 90.9 91.3 85.2 100.7 90.8 Methylphenidate (mean, [116.1, 118.0][90.0, 91.7] [91.0, 91.5] [85.0, 85.5] [100.3, 101.2] [89.4, 92.2] [95%CI]) Change in MAP (mean, +20.5 +8.3 +3.2 −1.4 +0.5 +7.4 95% CI) [19.5,21.5] [7.1, 9.5] [2.8, 3.7] [−2.0, −0.8] [−0.2, 1.2]  [5.8, 9.0] p-value<10⁻¹⁶ <10⁻¹⁶ <10⁻¹⁶ 1 0.07 <10⁻¹⁶

TABLE 5 Heart rate (HR, beats per minute) in individual animals duringisoflurane general anesthesia. CI = confidence interval, RR =respiratory rate. Animal 1 2 3 4 5 6 HR before 401.0 390.5 351.7 359.3357.6 361.3 methylphenidate (mean, [400.4, 401.7] [389.8, 391.2] [351.2,352.1] [357.9, 360.6] [357.1, 358.2] [360.4, 362.1] [95% CI) HR after 5mg/kg IV 386.8 383.3 365.5 360.0 +6.4 358.6 Methylphenidate (mean,[385.8, 388.4] [382.3, 384.4] [365.2, 365.9] [358.7, 361.3] [5.3, 7.5][357.8, 359.5] [95% CI]) Change in HR (mean, 95% −14.2 −7.2 +13.9 +0.72+0.5 −2.6 CI) [−15.9, −12.5] [−8.4, −5.9] [13.3, 14.5] [−1.19, 2.64] [−0.2, 1.2]  [−3.8, −1.4] p-value 1 1 <10⁻¹⁶ 0.2236 <10⁻¹⁶ 1

Example 5

In Examples 1-4, the inventors demonstrated that methylphenidate (MPH)actively induces emergence from isoflurane general anesthesia. Propofolis a widely used intravenous (IV) general anesthetic that may act bydifferent receptor mechanisms than isoflurane. Thus, the inventorsassessed if MPH induces emergence from other types of anesthesia, e.g.,propofol anesthesia.

For the first experiment, a lateral tail vein IV catheter was placed inrats under isoflurane anesthesia. After full recovery, propofol (8mg/kg) was administered IV and 45 sec later, MPH (5 mg/kg) or normalsaline (NS, vehicle) was injected IV. Time to emergence was defined asthe time until restoration of righting occurred. Statistical analysiswas performed using the Mann-Whitney test.

In the first experiment, time to emergence after a single dose ofpropofol was 747±58 sec (mean±SE) for rats that received NS (n=6), and433±24 sec (mean±SE) for rats that received MPH (n=6). The differencewas statistically significant (p=0.002).

For the second experiment, 2 IV catheters were placed and a continuouspropofol infusion was started in rats with pre-implanted EEG electrodes.After establishing the minimum plasma concentration of propofol requiredto maintain loss of righting, the second IV catheter was flushed withNS, and 5 minutes later MPH (5 mg/kg) was administered. In the secondexperiment with continuous propofol anesthesia, none of the ratsexhibited purposeful movements after injection of NS. After MPH,however, 5/6 rats exhibited signs of arousal and had restoration ofrighting within 4 min. One rat had a delayed arousal response withrestoration of righting 25 min after MPH. As shown in FIG. 8 , EEGspectral analysis demonstrated a shift in power from delta (<4 Hz) totheta (4-8 Hz) after administration of MPH during continuous propofolanesthesia.

Accordingly, the inventors demonstrated that MPH decreases time toemergence after a single dose of propofol, and produces both behavioraland neurophysiological evidence of arousal during continuous propofolanesthesia. MPH may be clinically useful as a reversal agent forpropofol.

Example 6

In this study, the inventors demonstrate that methylphenidate activelyinduces emergence from isoflurane anesthesia by increasing arousal. Inaddition, the inventors demonstrate using plethysmography and blood gasexperiments that methylphenidate also increases minute ventilation,which increases the rate of anesthetic elimination from the brain.²⁰Emergence from isoflurane anesthesia is dose dependent,²¹ thereforemethylphenidate-induced ventilatory stimulation likely contributes toaccelerating time to emergence.

The inventors protocol for testing loss of righting reflex did notutilize a rotating anesthetizing chamber, and the average dose ofisoflurane required to maintain loss of righting in this study was 0.9%.This dose was slightly higher than the dose previously reported for lossof righting in uninstrumented mice using a rotating anesthetizingchamber (0.81% isoflurane, with a 95% confidence interval between 0.78%and 0.84%).5 The stimulation provided by the temperature probe and theIV catheter in these rats was likely comparable to the stimulationprovided by the rotating anesthetizing chamber in uninstrumented mice.Electroencephalogram and plethysmography studies were performedseparately from behavioral experiments with some modifications in theexperimental protocols designed to minimize motion artifacts.Electroencephalogram studies performed under very similar experimentalconditions as the behavioral studies demonstrated a consistent shiftfrom delta to theta power within 30 seconds of methylphenidateadministration. These results agree with a previous study that reportedmethylphenidate induces a theta rhythm in rats anesthetized with chloralhydrate.²² The plethysmography experiments performed at a higher dose ofisoflurane (1.5%, or approximately 1 MAC) demonstrated increases inrespiratory rate and minute ventilation. Thus, the inventors demonstrateherein that these changes are similar to the changes that would havebeen observed in animals that regained the righting reflex in thebehavioral studies.

Cholinergic arousal pathways have been studied most extensively in thecontext of emergence from general anesthesia. Hudetz and colleagues³previously reported that intraventricular administration of thecholinesterase inhibitor neostigmine to rats during isofluraneanesthesia produced an increase in cross-approximate entropy of theelectroencephalogram, and elicited behavioral signs of arousal such asspontaneous limb movements and orofacial explorative movements Alkireand colleagues' previously reported that injection of nicotine into thecentral medial thalamus induced return of righting during continuousinhalation of sevoflurane, providing evidence for cholinergic pathwaysthat activate the thalamus inducing arousal from general anesthesia. Inpatients, physostigmine (PHY) has been reported to reduce post-operativesomnolence after halothane general anesthesia.²³ In studies involvinghuman volunteers, physostigmine (PHY) reversed propofol-induced loss ofconsciousness in 9 of 11 subjects,²⁴ and reversed sevoflurane-inducedloss of consciousness in 5 of 8 subjects.²⁵ Both of these studiesreported that administration of physostigmine produced significantincreases in auditory steady-state response and bispectral index, whichare neurophysiological correlates of increased arousal. Orexinergicarousal pathways have also been shown to play an important role inemergence from general anesthesia. Orexins are arousal-promoting peptideneurotransmitters released by neurons in the periformical area of thehypothalamus, and abnormal orexinergic signaling leads tonarcolepsy.^(26,27) Mesa and colleagues²⁸ have reported that a patientsuffering from narcolepsy underwent 3 different operations between 1979and 1995, and required 8-10 hours to emerge from general anesthesia eachtime. Kelz and colleagues⁵ reported in mice that both genetic andpharmacologic ablation of orexinergic signaling delays time to rightingafter discontinuation of isoflurane or sevoflurane general anesthesia.Interestingly, the inhaled anesthetic concentration required to produceloss of righting was unchanged in orexin-ablated mice compared towild-type, indicating that orexinergic neurons are not involved in themechanisms underlying induction of general anesthesia. In a separatestudy by Zecharia et al.,²⁹ intraventricular administration of orexin-Awas reported to reduce time to righting after propofol anddexmedetomidine administration.

Although there are several monoaminergic arousal pathways, they havebeen less well studied in the context of emergence from generalanesthesia. Luo and Leung⁶ have reported that injection of histamineinto the basal forebrain of rats decreased time to righting afterisoflurane general anesthesia, increased respiratory rate, and shiftedelectroencephalogram activity from a burst suppression pattern (“deep”general anesthesia) to a delta pattern (“lighter” general anesthesia).Their results suggest that enhanced histaminergic neurotransmission inthe basal forebrain may also play a role in emergence from generalanesthesia.

Decades ago, the clinical utility of methylphenidate as an analeptic,i.e. a central nervous system stimulant, was explored in psychiatry andanesthesiology 30 However, at that time, its mechanism of action wasunknown. Psychiatrists reported using the drug to promote arousal inpatients suffering from overdoses of antipsychotic nnedications,³¹ andto facilitate psychiatric interviewing.³² Studies conducted in theperioperative period suggested that methylphenidate promoted fasterrecovery after general anesthesia.³³³⁴ However, the onlyplacebo-controlled, double-blinded study reported no difference inrecovery time.³⁵ Prior to the United States Food and DrugAdministration's black box warning on droperidol in 2001, the drug waswidely used in anesthesiology practices as a sedative and antiemetic.The inventors demonstrate herein that the widespread use of droperidolmay have confounded the results of some of the earlier clinical studiesof methylphenidate (MPH). On the other hand, because methylphenidate(MPH) is now widely prescribed to treat attention deficit hyperactivitydisorder (ADHD), there are recent reports of increased anestheticrequirements in patients who take nnethylphenidate.^(36,37) Thesereports are consistent with the inventors discovery that methylphenidate(MPH) antagonizes isoflurane anesthesia. Methylphenidate (MPH) is knownto inhibit dopamine and norepinephrine transporters with similaraffinities (Ki=250 nM and 150 nM, respectively).⁷ Dopaminergic neuronsin the ventral tegmental area and substantia nigra pars compacta promotearousal, and play an important role in cognition and reward throughprojections to the thalamus, basal forebrain, nucleus accumbens, cortex,lateral dorsal tegmentum, and locus ceruleus.³⁸ A third cluster ofwake-active, dopaminergic neurons has been recently identified in theventral periaqueductal gray area.³⁹ There is recent evidence thatenhancement of dopaminergic neurotransmission increases ventilatorydrive in cats,⁴⁰⁻⁴².

Noradrenergic neurons in the locus ceruleus promote arousal throughprojections to the thalamus, basal forebrain, preoptic areas, andcortex,² and their inhibition is important in the sedative actions ofpropofol⁴³ and dexmedetomidine.⁴⁴ In addition, arousal-promotinghistaminergic neurons arising from the tuberomammillary nucleus may alsoplay a role in the actions of methylphenidate,⁸ although the mechanismsunderlying this pathway have yet to be clearly defined. Thereforemethylphenidate likely induces emergence by enhancing arousal promotingmonoaminergic (i.e. dopaminergic, noradrenergic, and possiblyhistaminergic) neurotransmission.

The inventors have demonstrated herein that administration of droperidolinhibits both the arousal-promoting effects and the increase in alveolarventilation induced by methylphenidate during isoflurane generalanesthesia. It has been reported that 3 mg/kg of droperidol has noeffect on isoflurane potency in rats,⁴⁵ and that the EC50 for loss ofrighting in mice is 40 mg/kg,⁴⁶ suggesting that the relatively modestrodent dose of 0.5 mg/kg had little impact on the anesthetic state ofthe animals in this study. This conjecture is further supported by thelack of electroencephalogram changes observed in the animals afterdroperidol administration. Droperidol is known primarily as anantagonist at D2 dopamine receptors, but it has also been shown toinhibit al adrenergic receptors.^(47,48) Therefore the inventors resultswith droperidol are consistent with the notion that dopaminergic andnoradrenergic neurotransmission play important roles in methylphenidateinduced emergence. Further studies will be necessary to elucidate whicharousal pathways are responsible for the specific actions ofmethylphenidate, although it is likely that the simultaneous activationof multiple monoaminergic arousal pathways contributes to its efficacy.

Because the molecular mechanisms underlying the actions of generalanesthetics are poorly understood, it has not been possible to designantagonists of general anesthetics. However, the inventors demonstratethat methylphenidate actively induces emergence from isofluraneanesthesia by stimulating monoaminergic arousal pathways. These resultsdemonstrate a novel approach for identifying clinically usefulantagonists of general anesthetics at the level of neural circuits.Methylphenidate has a well-established safety record in children andadults, through its more than two decades of use in the treatment ofAttention Deficit Hyperactivity Disorder (ADHD).⁷ The inventorsdemonstrate herein that intravenous methylphenidate could be used inadult and pediatric patients at the conclusion of surgery to reversegeneral anesthetic-induced unconsciousness and aid in the recovery ofcognitive function.

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The reference cited herein are incorporated herein in their entirety byreference.

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The invention claimed is:
 1. A computerized method for determining astate of consciousness using electroencephalogram (“EEG”) signalsacquired from electrodes configured to be coupled to a subjectexperiencing an administration of at least one anesthetic agent or atleast one drug to facilitate emergence from anesthesia, the computerizedmethod comprising: acquiring EEG data from the electrodes coupled to thesubject; applying at least one window to the EEG data; for the at leastone window, calculating a multi-taper spectrum estimation; and based onthe multi-taper spectrum estimation, generating an indicator about thestate of consciousness of the subject, wherein the indicator includes aspectrogram.
 2. The method of claim 1 further comprising determiningphysiological effects of the at least one anesthetic agent or at leastone drug to facilitate emergence from anesthesia using the spectrogramand indicating the physiological effects in the indicator.
 3. The methodof claim 2 wherein determining physiological effects includes comparingthe spectrogram to reference spectrograms.
 4. The method of claim 1further comprising determining a therapeutically effective amount of theat least one anesthetic agent or at least one drug to facilitateemergence from anesthesia using the indicator.
 5. The method of claim 4wherein determining a therapeutically effective amount includescomparing the indicator to reference reports.
 6. The method of claim 1wherein the sliding window has a duration of 2 seconds.
 7. The method ofclaim 1 wherein applying at least one window includes applying a slidingwindow stepped through a 0.05 second interval.
 8. The method of claim 1wherein applying at least one window includes applying a sliding window.9. The method of claim 1 wherein calculating the multi-taper spectrumestimation includes using 5 tapers.
 10. The method of claim 1 whereinapplying at least one window includes applying a sliding window.
 11. Themethod of claim 10 wherein the sliding window includes a duration of 2seconds.